Benzimidazole compounds as bradykinin antagonists

ABSTRACT

This invention relates to a heterocyclic compound of the formula: ##STR1## wherein a group of the formula: ##STR2## is a group of the formula: ##STR3## etc., X is O, S or N--R 5 , 
     R 1  is lower alkyl, etc., 
     R 5  is hydrogen, lower alkyl, etc., 
     R 2  is hydrogen, halogen, lower alkyl, etc., 
     R 3  is halogen, lower alkyl, etc., 
     R 4  is amino optionally having suitable substituent(s), and 
     A is lower alkylene, 
     and a salt thereof, to processes for preparation thereof, and to a pharmaceutical composition comprising the same for the prevention and/or the treatment of bradykinin or its analogues mediated diseases in human being or animals.

This application is a 371 PCT/JP95/01478 filed Jul. 25, 1995.

TECHNICAL FIELD

This invention relates to heterocyclic compounds and salts thereof whichhave activities as bradykinin antagonists and are useful for treatingseveral diseases.

One object of this invention is to provide heterocyclic compounds andsalts thereof which possess activities as bradykinin antagonists.

Another object of this invention is to provide processes for thepreparation of said heterocyclic compounds and salts thereof.

A further object of this invention is to provide a pharmaceuticalcomposition comprising, as an active ingredient, said heterocycliccompounds and salts thereof.

Still further object of this invention is to provide an agent for theprevention and/or the treatment of bradykinin or its analogues mediateddiseases such as allergy, inflammation, autoimmune disease, shock, pain,or the like, comprising said heterocyclic compounds and salts thereof asan active ingredient.

BACKGROUND ART

Heterocyclic compounds having activities as bradykinin antagonists havebeen known as described in EP-A-596,406 and EP-A-622,361.

DISCLOSURE OF THE INVENTION

The object heterocyclic compounds of this invention are new and can berepresented by the following general formula ##STR4## wherein a group ofthe formula: ##STR5## is a group of the formula: ##STR6## X is O, S orN--R⁵, R¹ is lower alkyl, halo(lower)alkyl, lower alkylamino (lower)alkyl, hydroxy(lower) alkyl, lower alkoxy(lower)alkyl, lower alkoxy,lower alkylthio, lower alkylamino, acyl(lower)alkyl, acyl, hydroxy,mercapto, aryl or ar(lower)alkyl, and

R⁵ is hydrogen, lower alkyl, halo(lower)alkyl, loweralkylamino(lower)alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl,lower alkoxy, lower alkylthio, lower alkylamino, acyl(lower)alkyl, acyl,aryl or ar(lower)alkyl, or

R¹ and R⁵ are taken together to form lower alkylene optionally having O,S or N or lower alkenylene optopnally having O, S or N,

R² is hydrogen, halogen, lower alkyl or lower alkoxy,

R³ is halogen, lower alkyl or lower alkoxy,

R⁴ is amino optionally having suitable substituent(s),

R⁸ is lower alkyl or acyl(lower)alkyl, and

A is lower alkylene.

The object compound [I] or its salt can be prepared by processes asillustrated in the following reaction schemes. ##STR7## wherein

R_(a) ¹ is lower alkoxy,

R⁶ is hydrogen or lower alkyl,

Ra⁷ is acyl having amino,

R_(b) ⁷ is acyl having acylamino,

Y is a leaving group, and

a group of the formula: ##STR8## R², R³, R⁴, R⁵ and A are each asdefined above.

In the above and subsequent description of the present specification andclaims, suitable examples of the various definitions to be includedwithin the scope of the invention are explained in detail in thefollowing.

The term "lower" is intended to mean a group having 1 to 6 carbonatom(s), unless otherwise provided.

In this respect, the term "lower" in lower alkenyl moiety, lower alkynylmoiety, heterocyclic(lower)alkenyl moiety and ar(lower)alkenyl moiety inthe various definitions is intended to mean a group having 2 to 6 carbonatoms.

Further, the term "lower" in lower alkenoyl moiety, lower alkynoylmoiety, cyclo(lower)alkyl moiety, cyclo(lower)alkenyl moiety,ar(lower)alkenoyl moiety, ar(lower)alkynoyl moiety andheterocyclic(lower)alkenoyl moiety in the various definitions isintended to mean a group having 3 to 6 carbon atoms.

Suitable "halogen" may be fluorine, chlorine, bromine and iodine.

Suitable "aryl" and aryl moiety in the term "ar(lower)alkenoyl" may bephenyl, naphthyl, phenyl substituted with lower alkyl [e.g. tolyl,xylyl, mesityl, cumenyl, di(tert-butyl)phenyl, etc.] and the like, inwhich preferable one is phenyl, naphthyl and tolyl.

Suitable "lower alkyl" and lower alkyl moiety in the terms"acyl(lower)alkyl", "lower alkylamino(lower)alkyl","hydroxy(lower)alkyl", "lower alkoxy(lower)alkyl","heterocyclic(lower)alkyl", "lower alkylthio" and "lower alkylamino" maybe straight or branched one such as methyl, ethyl, propyl, isopropyl,butyl, isobutyl, tert-butyl, pentyl, hexyl or the like, in whichpreferable one is C₁ -C₄ alkyl such as methyl, ethyl, propyl, isobutylor tert-butyl.

Suitable "lower alkoxy" and lower alkoxy moiety in the term "loweralkoxy(lower)alkyl" may be straight or branched one such as methoxy,ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, tert-butoxy, pentyloxy,hexyloxy or the like, in which preferable one is C₁ -C₄ alkoxy such asmethoxy, ethoxy or isopropoxy.

Suitable "lower alkylene" may be a straight or branched one such asmethylene, ethylene, trimethylene, methylmethylene, tetramethylene,ethylethylene, propylene, pentamethylene, hexamethylene or the like, inwhich the most preferable one is methylene.

Suitable "lower alkenylene" may be a straight or branched C₂ -C₆alkenylene such as vinylene, methylvinylene, propenylene,1,3-butadienylene, pentenylene or the like.

Suitable "halo(lower)alkyl" may be chloromethyl, dichloromethyl,bromomethyl, fluoromethyl, trifluoromethyl, pentafluoroethyl,trifluoroethyl or the like.

Suitable "ar(lower)alkyl" may be benzyl, phenethyl, phenylpropyl,naphthylmethyl or the like, in which the most preferable one is benzyl.

Suitable "heterocyclic group" and all heterocyclic moieties in thevarious definitions mentioned in this specification and claims such asin the term "heterocyclic(lower)alkyl", "hetrocyclic(lower)alkenyl","heterocyclic(lower)alkenoyl", etc., may include saturated orunsaturated, monocyclic or polycyclic one containing at least one heteroatom such as oxygen atom, sulfur atom and/or nitrogen atom, preferablyN, O and/or S containing heterocyclic group, in which preferable onesmay be morpholinyl, piperazinyl, pyridyl, tetrahydropyridyl,pyrimidinyl, piperidyl, thienyl, furyl, oxazolyl, isoxazolyl, thiazolyl,tetrazolyl, imidazolyl, pyrrolidinyl, pyrrolyl, quinolyl,tetrahydroquinolyl, isoquinolyl or the like.

Suitable "acyl" and acyl moiety in the term "acyl(lower)alkyl" may besubstituted or unsubstituted alkanoyl such as alkanoyl [e.g. formyl,acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl,hexanoyl, heptanoyl, 3,3-dimethylbutyryl, etc.], halo(lower)alkanoyl[e.g. chloroacetyl, trifluoroacetyl, bromoacetyl, bromobutyryl,heptafluorobutyryl, etc.], hydroxy(lower)alkanoyl [e.g. glycoloyl,lactoyl, 3-hydroxypropionyl, glyceroyl, etc.], loweralkylsulfonyloxy(lower)alkanoyl [e.g. mesyloxyacetyl,ethylsulfonyloxyacetyl, mesyloxypropionyl, etc.], loweralkoxy(lower)alkanoyl [e.g. methoxyacetyl, ethoxyacetyl,methoxypropionyl, ethoxypropionyl, propoxypropionyl, methoxybutyryl,etc.], lower alkylthio(lower)alkanoyl [e.g. methylthioacetyl,ethylthioacetyl, methylthiopropionyl, ethylthiopropionyl,propylthiopropionyl, methylthiobutyryl, etc.], loweralkanoyloxy(lower)alkanoyl [e.g. acetyloxyacetyl, acetyloxypropionyl,propionyloxyacetyl, etc.], aryloxy(lower)alkanoyl [e.g. phenyloxyacetyl,phenyloxypropionyl, tolyloxyacetyl, naphthyloxyacetyl, etc.],aroyl(lower)alkanoyl [e.g. phenyloxalyl, benzoylacetyl,benzoylpropionyl, etc.], carboxy(lower)alkanoyl [e.g. oxalo,carboxyacetyl, 3-carboxypropionyl, 3-carboxybutyryl, 4-carboxybutyryl,4-carboxyvaleryl, etc.], esterified carboxy(lower)alkanoyl, for example,lower alkoxycarbonyl(lower)alkanoyl [e.g. methoxycarbonylacetyl,ethoxycarbonylacetyl, methoxycarbonylpropionyl, ethoxycarbonylpropionyl,etc.], carbamoyl(lower)alkanoyl [e.g. carbamoylacetyl,carbamoylpropionyl, etc.], lower alkylcarbamoyl(lower)alkanoyl [e.g.methylcarbamoylacetyl, methylcarbamoylpropionyl,ethylcarbamoylpropionyl, dimethylcarbamoylpropionyl,(N-methyl-N-ethylcarbamoyl)propionyl, etc.], ar(lower)alkanoyl [e.g.phenylacetyl, tolylacetyl, naphthylacetyl, 2-phenylpropionyl,3-phenylpropionyl, 4-phenylbutyryl, tritylcarbonyl, etc.], optionallysubstituted heterocyclic(lower)alkanoyl [e.g. morpholinoacetyl,thiomorpholinoacetyl, morpholinopropionyl, thiomorpholinopropionyl,piperidinopropionyl, piperazinylpropionyl, pyridylacetyl,pyrrolidinylpropionyl, imidazolidinylpropionyl, piperidinoacetyl,pyrrolidinylacetyl, hexamethyleneiminoacetyl,hexamethyleneiminopropionyl, imidazolylacetyl, furylacetyl,thienylacetyl, methylpiperazinylacetyl, pyridylpiperazinylacetyl, etc.],heterocyclicthio(lower)alkanoyl [e.g. pyridylthioacetyl,pyrimidinylthioacetyl, imidazolylthiopropionyl, etc.], etc., loweralkenoyl [e.g. acryloyl, crotonoyl, isocrotonoyl, 3-butenoyl,3-pentenoyl, 4-pentenoyl, methacryloyl, etc.], lower alkynoyl [e.g.propioloyl, 2-butynoyl, 3-butynoyl, etc.], cyclo(lower)alkylcarbonyl[e.g. cyclopropylcarbonyl, cyclobutylcarbonyl, cyclopentylcarbonyl,cyclohexylcarbonyl, etc.], cyclo(lower)alkenylcarbonyl [e.g.cyclopentenylcarbonyl, cyclohexenylcarbonyl, etc.], carboxy, esterifiedcarboxy such as lower alkoxycarbonyl [e.g. methoxycarbonyl,ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl,isobutoxycarbonyl, tert-butoxycarbonyl, pentyloxycarbonyl,hexyloxycarbonyl, etc.], aryloxycarbonyl [e.g. phenoxycarbonyl, etc.],etc., substituted or unsubstituted aroyl such as aroyl [e.g. benzoyl,toluoyl, xyloyl, naphthoyl, etc.], lower alkoxyaroyl [e.g.methoxybenzoyl, etc.], haloaroyl [e.g. chlorobenzoyl, fluorobenzoyl,etc.], acylaroyl, for example, lower alkoxycarbonylaroyl [e.g.methoxycarbonylbenzoyl, etc.], etc., substituted or unsubstitutedar(lower)alkenoyl, in which said aryl group may be substituted with theabove-mentioned lower alkyl or lower alkoxy, such as ar(lower)alkenoyl[e.g. cinnamoyl, allocinnamoyl, α-methylcinnamoyl, 4-methylcinnamoyl,etc.], lower alkoxy-ar(lower)alkenoyl [e.g. methoxycinnamoyl,ethoxycinnamoyl, dimethoxycinnamoyl, etc.], loweralkylenedioxy-ar(lower)alkenoyl [e.g. methylenedioxycinnamoyl,ethylenedioxycinnamoyl, etc.], nitro-ar(lower)alkenoyl [e.g.nitrocinnamoyl, etc.], cyano-ar(lower)alkenoyl [e.g. cyanocinnamoyl,etc.], halo-ar(lower)alkenoyl [e.g. chlorocinnamoyl, fluorocinnamoyl,etc.], hydroxy-ar(lower)alkenoyl [e.g. hydroxycinnamoyl, etc.],hydroxy(lower)alkoxy-ar(lower)alkenoyl [e.g. hydroxymethoxycinnamoyl,hydroxyethoxycinnamoyl, etc.], amino(lower)alkoxy-ar(lower)alkenoyl[e.g. aminoethoxycinnamoyl, etc.], loweralkylamino(lower)alkoxy-ar(lower)alkenoyl [e.g.methylaminomethoxycinnamoyl, dimethylaminomethoxycinnamoyl, etc.],heterocyclic(lower)alkoxy-ar(lower)alkenoyl [e.g.pyridylmethoxycinnamoyl, etc.], optionally substitutedheterocyclic-ar(lower)alkenoyl [e.g. morpholinocinnamoyl,methylpiperazinylcinnamoyl, pyrrolidinylcinnamoyl,oxopyrrolidinylcinnamoyl, oxopiperidinocinnamoyl,dioxopyrrolidinylcinnamoyl, oxooxazolidinylcinnamoyl, pyrrolylcinnamoyl,tetrazolylcinnamoyl, etc.], heterocyclic(lower)alkyl-ar(lower)alkenoyl[e.g. pyridylmethylcinnamoyl, pyridylethylcinnamoyl,quinolylethylcinnamoyl, etc.], heterocyclic(lower)alkenyl-ar(lower)alkenoyl [e.g. pyridylvinylcinnamoyl, quinolylvinylcinnamoyl,etc.], amino-ar(lower)alkenoyl [e.g. aminocinnamoyl, etc.], loweralkylamino-ar(lower)alkenoyl [e.g. methylaminocinnamoyl,dimethylaminocinnamoyl, etc.], acylamino-ar(lower)alkenoyl, for example,lower alkanoylamino-ar(lower)alkenoyl [e.g. acetylaminocinnamoyl,propionylaminocinnamoyl, isobutyrylaminocinnamoyl, etc.],cycloalkyl(lower)alkanoylamino-ar(lower)alkenoyl [e.g.cyclopentylacetylaminocinnamoyl, cyclohexylacetylaminocinnamoyl,adamantylacetylaminocinnamoyl, etc.],cycloalkylcarbonylamino-ar(lower)alkenoyl [e.g.cyclopropylcarbonylaminocinnamoyl, cyclopentylcarbonylaminocinnamoyl,cyclohexylcarbonylaminocinnamoyl, adamantylcarbonylaminocinnamoyl,etc.], lower alkenoylamino-ar(lower)alkenoyl [e.g.acryloylaminocinnamoyl, crotonoylaminocinnamoyl, etc.], loweralkoxycarbonylamino-ar (lower)alkenoyl [e.g.methoxycarbonylaminocinnamoyl, ethoxycarbonylaminocinnamoyl, etc.],hydroxy(lower)alkanoylamino-ar(lower)alkenoyl [e.g.hydroxyacetylaminocinnamoyl, hydroxypropionylaminocinnamoyl, etc.],lower alkoxy(lower)alkanoylamino-ar(lower)alkenoyl [e.g.methoxyacetylaminocinnamoyl, methoxypropionylaminocinnamoyl, etc.],halo(lower)alkanoylamino-ar(lower)alkenoyl [e.g.chloroacetylaminocinnamoyl, bromobutyrylaminocinnamoyl,trifluoroacetylaminocinnamoyl, etc.],amino(lower)alkanoylamino-ar(lower)alkenoyl [e.g.aminoacetylaminocinnamoyl, aminopropionylaminocinnamoyl, etc.], loweralkylamino(lower)alkanoylamino-ar(lower)-alkenoyl [e.g.methylaminoacetylaminocinnamoyl, dimethylaminoacetylaminocinnamoyl,etc.], lower alkanoylamino(lower)alkanoylamino-ar(lower)alkenoyl [e.g.acetylaminoacetylaminocinnamoyl, acetylaminopropionylaminocinnamoyl,etc.], carboxy(lower)alkanoylamino-ar(lower)alkenoyl [e.g.carboxyacetylaminocinnamoyl, carboxypropionylaminocinnamoyl, etc.],lower alkoxycarbonyl(lower)alkanoylamino-ar(lower)alkenoyl [e.g.ethoxycarbonylacetylaminocinnamoyl,ethoxycarbonylpropionylaminocinnamoyl, etc.], loweralkoxycarbonyl(lower)alkenoylamino-ar(lower)alkenoyl [e.g.ethoxycarbonylacryloylaminocinnamoyl, etc.],halo(lower)alkoxycarbonylamino-ar(lower)alkenoyl [e.g.chloroethoxycarbonylaminocinnamoyl, etc.], optionally substitutedheterocyclic(lower)alkanoylamino-ar(lower)-alkenoyl [e.g.pyridylacetylaminocinnamoyl, thienylacetylaminocinnamoyl,methylpyrrolylacetylaminocinnamoyl, etc.], aroylamino-ar(lower)alkenoyl[e.g. benzoylaminocinnamoyl, etc.], optionally substitutedheterocycliccarbonylamino-ar(lower)alkenoyl [e.g.pyridylcarbonylaminocinnamoyl, morpholinocarbonylaminocinnamoyl,furylcarbonylaminocinnamoyl, thienylcarbonylaminocinnamoyl,oxazolylcarbonylaminocinnamoyl, methyloxazolylcarbonylaminocinnamoyl,dimethylisoxazolylcarbonylaminocinnamoyl,imidazolylcarbonylaminocinnamoyl,methylimidazolylcarbonylaminocinnamoyl, piperidylcarbonylaminocinnamoyl,ethylpiperidylcarbonylaminocinnamoyl,acetylpiperidylcarbonylaminocinnamoyl,pyrrolidinylcarbonylaminocinnamoyl,acetylpyrrolidinylcarbonylaminocinnamoyl,tert-butoxycarbonylpyrrolidinylcarbonylaminocinnamoyl, etc.], loweralkylsulfonylamino-ar(lower)alkenoyl [e.g. mesylaminocinnamoyl,ethylsulfonylaminocinnamoyl, etc.], etc., N-(lower alkanoyl)-N-(loweralkyl)amino-ar(lower)alkenoyl [e.g. N-acetyl-N-methylaminocinnamoyl,N-acetyl-N-ethylaminocinnamoyl, N-propionyl-N-methylaminocinnamoyl,etc.], N-[lower alkoxy(lower)-alkanoyl]-N-(loweralkyl)amino-ar(lower)alkenoyl [e.g.N-methoxyacetyl-N-methylaminocinnamoyl,N-methoxypropionyl-N-methylaminocinnamoyl, etc.], N-(loweralkanoyl)-N-[heterocyclic(lower)alkyl]amino-ar(lower)alkenoyl [e.g.N-acetyl-N-pyridylmethylaminocinnamoyl, etc.], N-(loweralkanoyl)-N-[lower alkoxy(lower)alkyl]amino-ar(lower)alkenoyl [e.g.N-acetyl-N-methoxyethylaminocinnamoyl,N-acetyl-N-methoxymethylaminocinnamoyl,N-propionyl-N-methoxyethylaminocinnamoyl, etc.], N-(loweralkanoyl)-N-[lower alkoxycarbonyl(lower)alkyl]-amino-ar(lower)alkenoyl[e.g. N-acetyl-N-tert-butoxycarbonylmethylaminocinnamoyl,N-acetyl-N-tert-butoxycarbonylethylaminocinnamoyl,N-propionyl-N-tert-butoxycarbonylmethylaminocinnamoyl, etc.], N-(loweralkanoyl)-N-[carboxy(lower)alkyl]amino-ar(lower)alkenoyl [e.g.N-acetyl-N-carboxymethylaminocinnamoyl,N-acetyl-N-carboxyethylaminocinnamoyl,N-propionyl-N-carboxymethylaminocinnamoyl, etc.], N-[loweralkoxy(lower)alkanoyl]-N-[heterocyclic(lower)alkyl]amino-ar(lower)alkenoyl[e.g. N-methoxyacetyl-N-pyridylmethylaminocinnamoyl,N-methoxypropionyl-N-pyridylmethylaminocinnamoyl, etc.],N-[heterocycliccarbonyl]-N-[loweralkoxy(lower)alkyl]amino-ar(lower)alkenoyl [e.g.N-pyridylcarbonyl-N-methoxymethylaminocinnamoyl,N-pyridylcarbonyl-N-methoxyethylaminocinnamoyl,N-thienylcarbonyl-N-methoxyethylaminocinnamoyl, etc.],ureido-ar(lower)alkenoyl [e.g. ureidocinnamoyl, etc.], loweralkylureido-ar(lower)alkenoyl [e.g. methylureidocinnamoyl,ethylureidocinnamoyl, dimethylureidocinnamoyl, etc.],heterocyclicureido-ar(lower)alkenoyl [e.g. pyridylureidocinnamoyl,pyrimidinylureidocinnamoyl, thienylureidocinnamoyl, etc.],acyl-ar(lower)alkenoyl, for example, lower alkanoyl-ar(lower)alkenoyl[e.g. formylcinnamoyl, acetylcinnamoyl, propionylcinnamoyl, etc.],carboxy-ar(lower)alkenoyl [e.g. carboxycinnamoyl, etc.], loweralkoxycarbonyl-ar(lower)alkenoyl [e.g. methoxycarbonylcinnamoyl,ethoxycarbonylcinnamoyl, etc.], carbamoyl-ar(lower)alkenoyl [e.g.carbamoylcinnamoyl, etc.], lower alkylcarbamoyl-ar(lower)alkenoyl [e.g.methylcarbamoylcinnamoyl, ethylcarbamoylcinnamoyl,dimethylcarbamoylcinnamoyl, propylcarbamoylcinnamoyl,isopropylcarbamoylcinnamoyl, diethylcarbamoylcinnamoyl,N-methyl-N-ethylcarbamoylcinnamoyl, etc.],hydroxy(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.hydroxyethylcarbamoylcinnamoyl, bis(hydroxyethyl)carbamoylcinnamoyl,etc.], N-[hydroxy(lower)alkyl]-N-(loweralkyl)carbamoyl-ar(lower)alkenoyl [e.g.N-hydroxyethyl-N-methylcarbamoylcinnamoyl, etc.], loweralkoxy(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.methoxymethylcarbamoylcinnamoyl, methoxyethylcarbamoylcinnamoyl,bis(methoxyethyl)carbamoylcinnamoyl, ethoxyethylcarbamoylcinnamoyl,methoxypropylcarbamoylcinnamoyl, bis(ethoxyethyl)carbamoylcinnamoyl,etc.], N-[lower alkoxy(lower)alkyl]-N-(loweralkyl)carbamoyl-ar(lower)alkenoyl [e.g.N-methoxyethyl-N-methylcarbamoylcinnamoyl,N-ethoxyethyl-N-methylcarbamoylcinnamoyl, etc.],heterocyclic(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.pyridylmethylcarbamoylcinnamoyl, furylmethylcarbamoylcinnamoyl,thienylmethylcarbamoylcinnamoyl, etc.],N-[heterocyclic(lower)alkyl]-N-(lower alkyl) carbamoyl-ar(lower)alkenoyl [e.g. N-pyridylmethyl-N-methylcarbamoylcinnamoyl, etc.],heterocycliccarbamoyl-ar(lower)alkenoyl [e.g.morpholinylcarbamoylcinnamoyl, thienylcarbamoylcinnamoyl,pyridylcarbamoylcinnamoyl, pyrimidinylcarbamoylcinnamoyl,tetrazolylcarbamoylcinnamoyl, etc.], optionally substitutedheterocycliccarbonyl-ar(lower)alkenoyl [e.g.morpholinocarbonylcinnamoyl, pyrrolidinylcarbonylcinnamoyl,piperidinocarbonylcinnamoyl, tetrahydropyridylcarbonylcinnamoyl,methylpiperazinylcarbonylcinnamoyl, etc.], loweralkenylcarbamoyl-ar(lower)alkenoyl [e.g. vinylcarbamoylcinnamoyl,allylcarbamoylcinnamoyl, methylpropenylcarbamoylcinnamoyl, etc.], loweralkynylcarbamoyl-ar(lower)alkenoyl [e.g. ethynylcarbamoylcinnamoyl,propynylcarbamoylcinnamoyl, etc.],amino(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.aminomethylcarbamoylcinnamoyl, aminoethylcarbamoylcinnamoyl, etc.],lower alkylamino(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.methylaminomethylcarbamoylcinnamoyl, methylaminoethylcarbamoylcinnamoyl,ethylaminoethylcarbamoylcinnamoyl, dimethylaminoethylcarbamoylcinnamoyl,etc.], lower alkylcarbamoyloxy(lower)alkylcarbamoyl-ar(lower)alkenoyl[e.g. methylcarbamoyloxymethylcarbamoylcinnamoyl,methylcarbamoyloxyethylcarbamoylcinnamoyl,ethylcarbamoyloxyethylcarbamoylcinnamoyl,dimethylcarbamoyloxyethylcarbamoylcinnamoyl, etc.], loweralkylcarbamoyl(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.methylcarbamoylmethylcarbamoylcinnamoyl,methylcarbamoylethylcarbamoylcinnamoyl,ethylcarbamoylethylcarbamoylcinnamoyl,dimethylcarbamoylethylcarbamoylcinnamoyl, etc.], loweralkoxycarbonyl(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.methoxycarbonylmethylcarbamoylcinnamoyl,methoxycarbonylethylcarbamoylcinnamoyl,ethoxycarbonylmethylcarbamoylcinnamoyl,ethoxycarbonylethylcarbamoylcinnamoyl, etc.],carboxy(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.carboxymethylcarbamoylcinnamoyl, carboxyethylcarbamoylcinnamoyl, etc.],[lower alkylcarbamoyl-ar(lower)alkyl]carbamoyl-ar(lower)alkenoyl [e.g.(methylcarbamoyl-phenethyl)carbamoylcinnamoyl,(ethylcarbamoyl-phenethyl)carbamoylcinnamoyl, etc.], [loweralkoxycarbonyl-ar(lower)alkyl]carbamoyl-ar(lower)alkenoyl [e.g.(methoxycarbonyl-phenethyl)-carbamoylcinnamoyl,(ethoxycarbonyl-phenethyl)-carbamoylcinnamoyl, etc.],[carboxy-ar(lower)alkyl]carbamoyl-ar(lower)alkenoyl [e.g.carboxy-phenethyl)carbamoylcinnamoyl, etc.], N-[loweralkylcarbamoyl(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl[e.g. N-(methylcarbamoylmethyl)-N-methylcarbamoylcinnamoyl,N-(methylcarbamoylethyl)-N-methylcarbamoylcinnamoyl,N-(ethylcarbamoylethyl)-N-methylcarbamoylcinnamoyl,N-(dimethylcarbamoylethyl)-N-methylcarbamoylcinnamoyl, etc.], N-[loweralkoxycarbonyl(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl[e.g. N-methoxycarbonylmethyl-N-methylcarbamoylcinnamoyl,N-methoxycarbonylethyl-N-methylcarbamoylcinnamoyl,N-ethoxycarbonylmethyl-N-methylcarbamoylcinnamoyl,N-ethoxycarbonylethyl-N-methylcarbamoylcinnamoyl, etc.],N-[carboxy(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl [e.g.N-carboxymethyl-N-methylcarbamoylcinnamoyl,N-carboxyethyl-N-methylcarbamoylcinnamoyl, etc.],arylcarbamoyl-ar(lower)alkenoyl [e.g. phenylcarbamoylcinnamoyl,naphthylcarbamoylcinnamoyl, etc.], etc., etc., ar(lower)alkynoyl [e.g.phenylpropioloyl, etc.], substituted or unsubstitutedheterocyclic(lower)alkenoyl, in which said heterocyclic group may besubstituted with the above-mentioned lower alkyl or lower alkoxy, suchas heterocyclic(lower)alkenoyl [e.g. morpholinylacryloyl,pyridylacryloyl, thienylacryloyl, etc.],heterocyclic(lower)alkyl-heterocyclic(lower)alkenoyl [e.g.pyridylmethylpyridylacryloyl, pyridylethylpyridylacryloyl,quinolylethylpyridylacryloyl, etc.],heterocyclic(lower)alkenyl-heterocyclic(lower)alkenoyl [e.g.pyridylvinylpyridylacryloyl, quinolylvinylpyridylacryloyl, etc.],amino-heterocyclic(lower)alkenoyl [e.g. aminopyridylacryloyl, etc.],lower alkylamino-heterocyclic(lower)alkenoyl [e.g.methylaminopyridylacryloyl, dimethylaminopyridylacryloyl, etc.],acylamino-heterocyclic(lower)alkenoyl, for example, loweralkanoylamino-heterocyclic(lower)alkenoyl [e.g.acetylaminopyridylacryloyl, propionylaminopyridylacryloyl, etc.], loweralkenoylamino-heterocyclic(lower)alkenoyl [e.g.acryloylaminopyridylacryloyl, crotonoylaminopyridylacryloyl, etc.],heterocyclic(lower)alkanoylamino-heterocyclic(lower)-alkenoyl [e.g.pyridylacetylaminopyridylacryloyl, thienylacetylaminopyridylacryloyl,etc.], heterocycliccarbonylamino-heterocyclic(lower)alkenoyl which maybe substituted with lower alkyl [e.g.pyridylcarbonylaminopyridylacryloyl, furylcarbonylaminopyridylacryloyl,methylpyridylcarbonylaminopyridylacryloyl, etc.], loweralkanoylamino(lower)alkanoylamino-heterocyclic(lower)-alkenoyl [e.g.acetylaminoacetylaminopyridylacryloyl,acetylaminopropionylaminopyridylacryloyl, etc.], loweralkoxycarbonyl(lower)alkanoylamino-heterocyclic(lower)-alkenoyl [e.g.ethoxycarbonylacetylaminopyridylacryloyl,ethoxycarbonylpropionylaminopyridylacryloyl, etc.], loweralkoxy(lower)alkanoylamino-heterocyclic(lower)alkenoyl [e.g.methoxyacetylaminopyridylacryloyl,methoxypropionyl-aminopyridylacryloyl,ethoxypropionylaminopyridylacryloyl, etc.], etc., loweralkylureido-heterocyclic(lower)alkenoyl [e.g.methylureidopyridylacryloyl, etc.], acyl-heterocyclic(lower)alkenoyl,for example, carboxyheterocyclic(lower)alkenoyl [e.g.carboxypyridylacryloyl, etc.], loweralkoxycarbonyl-heterocyclic(lower)alkenoyl [e.g.ethoxycarbonylpyridylacryloyl, etc.], loweralkanoyl-heterocyclic(lower)alkenoyl [e.g. acetylpyridylacryloyl,acetyltetrahydroquinolylacryloyl,etc.], loweralkylcarbamoyl-heterocyclic(lower)alkenoyl [e.g.methylcarbamoylpyridylacryloyl, ethylcarbamoylpyridylacryloyl,dimethylcarbamoylpyridylacryloyl, diethylcarbamoylpyridylacryloyl,isopropylcarbamoylpyridylacryloyl,N-ethyl-N-methylcarbamoylpyridylacryloyl, etc.], loweralkoxy(lower)alkylcarbamoyl-heterocyclic(lower)alkenoyl [e.g.methoxymethylcarbamoylpyridylacryloyl,methoxyethylcarbamoylpyridylacryloyl,methoxypropylcarbamoylpyridylacryloyl,ethoxyethylcarbamoylpyridylacryloyl,bis(methoxyethyl)carbamoylpyridylacryloyl, etc.],hydroxy(lower)alkylcarbamoyl-heterocyclic(lower)alkenoyl [e.g.hydroxymethylcarbamoylpyridylacryloyl,hydroxyethylcarbamoylpyridylacryloyl,bis(hydroxyethyl)carbamoylpyridylacryloyl, etc.],heterocycliccarbamoyl-heterocyclic(lower)alkenoyl [e.g.pyridylcarbamoylpyridylacryloyl, morpholinylcarbamoylpyridylacryloyl,thienylcarbamoylpyridylacryloyl, pyrimidinylcarbamoylpyridylacryloyl,etc.], heterocyclic(lower)alkylcarbamoyl-heterocyclic(lower)-alkenoyl[e.g. pyridylmethylcarbamoylpyridylacryloyl,furylmethylcarbamoylpyridylacryloyl,thienylmethylcarbamoylpyridylacryloyl, etc.],heterocycliccarbonyl-heterocyclic(lower)alkenoyl [e.g.morpholinocarbonylpyridylacryloyl, pyrrolidinylcarbonylpyridylacryloyl,piperidinocarbonylpyridylacryloyl, etc.], loweralkenylcarbamoyl-heterocyclic(lower)alkenoyl [e.g.vinylcarbamoylpyridylacryloyl, allylcarbamoylpyridylacryloyl, etc.],lower alkynylcarbamoyl-heterocyclic(lower)alkenoyl [e.g.ethynylcarbamoylpyridylacryloyl, propynylcarbamoylpyridylacryloyl,etc.], etc., etc., heterocycliccarbonyl which may be substituted withsubstituent [e.g. furoyl, thenoyl, nicotinoyl, isonicotinoyl,morpholinocarbonyl, piperidinocarbonyl, 4-methyl-1-piperazinylcarbonyl,4-ethyl-1-piperazinylcarbonyl, dimethylaminopiperidinocarbonyl,4-methylcarbamoyl-1-piperazinylcarbonyl,1,2,3,6-tetrahydropyridylcarbonyl, pyrrolidinylcarbonyl,indolylcarbonyl, etc.], aryloxycarbonyl which may be substituted withnitro [e.g. phenyloxycarbonyl, nitrophenyloxycarbonyl, etc.],ar(lower)alkoxycarbonyl which may be substituted with nitro [e.g.benzyloxycarbonyl, nitrobenzyloxycarbonyl, etc.], substituted orunsubstituted carbamoyl or thiocarbamoyl such as carbamoyl, loweralkylcarbamoyl [e.g. methylcarbamoyl, ethylcarbamoyl, propylcarbamoyl,isopropylcarbamoyl, butylcarbamoyl, isobutylcarbamoyl,tert-butylcarbamoyl, pentylcarbamoyl, dimethylcarbamoyl,diethylcarbamoyl, N-ethyl-N-methylcarbamoyl, etc.],carboxy(lower)alkylcarbamoyl [e.g. carboxymethylcarbamoyl,carboxyethylcarbamoyl, etc.], esterified carboxy(lower)alkylcarbamoyl,for example, lower alkoxycarbonyl(lower)alkylcarbamoyl [e.g.methoxycarbonylmethylcarbamoyl, ethoxycarbonylmethylcarbamoyl,ethoxycarbonylethylcarbamoyl, etc.], lower alkenylcarbamoyl [e.g.vinylcarbamoyl, allylcarbamoyl, etc.], cyclo(lower)alkylcarbamoyl [e.g.cyclopropylcarbamoyl, cyclobutylcarbamoyl, cyclopentylcarbamoyl,cyclohexylcarbamoyl, etc.], halo(lower)alkanoylcarbamoyl [e.g.trichloroacetylcarbamoyl, etc.], substituted or unsubstitutedarylcarbamoyl, for example, arylcarbamoyl [e.g. phenylcarbamoyl,tolylcarbamoyl, xylylcarbamoyl, naphthylcarbamoyl, ethylphenylcarbamoyl,etc.], arylthiocarbamoyl [e.g. phenylthiocarbamoyl, etc.], loweralkoxy-arylcarbamoyl [e.g. methoxyphenylcarbamoyl, etc.],halo-arylcarbamoyl [e.g. fluorophenylcarbamoyl, chlorophenylcarbamoyl,etc.], halo(lower)alkyl-arylcarbamoyl [e.g.trifluoromethylphenylcarbamoyl, etc.], nitro-arylcarbamoyl [e.g.nitrophenylcarbamoyl, etc.], cyanoarylcarbamoyl [e.g.cyanophenylcarbamoyl, etc.], hydroxy(lower)alkyl-arylcarbamoyl [e.g.hydroxymethylphenylcarbamoyl, hydroxyethylphenylcarbamoyl, etc.],aminoarylcarbamoyl [e.g. aminophenylcarbamoyl, etc.], loweralkylaminoarylcarbamoyl [e.g. methylaminophenylcarbamoyl,ethylaminophenylcarbamoyl, dimethylaminophenylcarbamoyl, etc.], loweralkanoylamino-arylcarbamoyl [e.g. acetylaminophenylcarbamoyl,propionylaminophenylcarbamoyl, etc.], N-(lower alkanoyl)-N-(loweralkyl)amino-arylcarbamoyl [e.g. N-acetyl-N-methylaminophenylcarbamoyl,N-propionyl-N-methylaminophenylcarbamoyl, etc.], loweralkoxy(lower)alkanoylamino-arylcarbamoyl [e.g.methoxyacetylaminophenylcarbamoyl, methoxypropionylaminophenylcarbamoyl,etc.], lower alkoxycarbonyl(lower)alkanoylamino-arylcarbamoyl [e.g.ethoxycarbonylacetylaminophenylcarbamoyl,methoxycarbonylpropionylaminophenylcarbamoyl, etc.],carboxyamino-arylcarbamoyl [e.g. carboxyaminophenylcarbamoyl, etc.],lower alkoxycarbonylamino-arylcarbamoyl [e.g.ethoxycarbonylaminophenylcarbamoyl, etc.],heterocycliccarbonylamino-arylcarbamoyl [e.g.pyridylcarbonylaminophenylcarbamoyl, furylcarbonylaminophenylcarbamoyl,morpholinocarbonylaminophenylcarbamoyl, etc.],heterocyclic(lower)alkanoylamino-arylcarbamoyl [e.g.pyridylacetylaminophenylcarbamoyl, thienylacetylaminophenylcarbamoyl,etc.], aroylaminoarylcarbamoyl [e.g. benzoylaminophenylcarbamoyl, etc.],ureido-arylcarbamoyl [e.g. ureidophenylcarbamoyl, etc.], loweralkylureido-arylcarbamoyl [e.g. methylureidophenylcarbamoyl,ethylureidophenylcarbamoyl, etc.],hydroxyimino(lower)alkyl-arylcarbamoyl [e.g.hydroxyiminoethylphenylcarbamoyl, etc.], loweralkoxyimino(lower)alkyl-arylcarbamoyl [e.g.methoxyiminoethylphenylcarbamoyl, etc.], loweralkylhydrazono(lower)alkyl-arylcarbamoyl [e.g.methylhydrazonoethylphenylcarbamoyl,dimethylhydrazonoethylphenylcarbamoyl, etc.], optionally substitutedheterocyclic-arylcarbamoyl [e.g. oxopyrrolidinylphenylcarbamoyl,oxopiperidinophenylcarbamoyl, dioxopyrrolidinylphenylcarbamoyl,oxooxazolidinylphenylcarbamoyl, pyrrolylphenylcarbamoyl, etc.],acyl-arylcarbamoyl, for example, carboxy-arylcarbamoyl [e.g.carboxyphenylcarbamoyl, etc.], lower alkoxycarbonyl-arylcarbamoyl [e.g.ethoxycarbonylphenylcarbamoyl, etc.], heterocycliccarbonyl-arylcarbamoyl[e.g. morpholinocarbonylphenylcarbamoyl,pyrrolidinylcarbonylphenylcarbamoyl, piperidinocarbonylphenylcarbamoyl,1,2,3,6-tetrahydropyridylcarbonylphenylcarbamoyl,piperazinylcarbonylphenylcarbamoyl,thiomorpholinocarbonylphenylcarbamoyl, etc.],heterocycliccarbonyl-arylcarbamoyl substituted with lower alkyl [e.g.methylpiperazinylcarbonylphenylcarbamoyl,ethylpiperazinylcarbonylphenylcarbamoyl, etc.],heterocycliccarbonyl-arylcarbamoyl substituted with aryl [e.g.phenylpiperazinylcarbonylphenylcarbamoyl, etc.],heterocycliccarbonyl-arylcarbamoyl substituted with a heterocyclic group[e.g. pyridylpiperazinylcarbonyl-phenylcarbamoyl, etc.],heterocycliccarbonyl-arylcarbamoyl substituted with lower alkanoyl [e.g.acetylpiperazinyl-carbonylphenylcarbamoyl, etc.],heterocycliccarbonyl-arylcarbamoyl substituted with lower alkoxycarbonyl[e.g. ethoxycarbonylpiperazinylcarbonylphenylcarbamoyl, etc.],heterocycliccarbonyl-arylcarbamoyl substituted with lower alkylamino[e.g. methylaminopiperazinylcarbonyl-phenylcarbamoyl,dimethylaminopiperidinocarbonylphenyl-carbamoyl, etc.],heterocycliccarbonyl-arylcarbamoyl substituted with lower alkylcarbamoyl[e.g. methylcarbamoylpiperazinylcarbonylphenylcarbamoyl, etc.],carbamoyl-arylcarbamoyl [e.g. carbamoylphenylcarbamoyl, etc.], loweralkylcarbamoyl-arylcarbamoyl [e.g. methylcarbamoylphenylcarbamoyl,ethylcarbamoylphenyl-carbamoyl, propylcarbamoylphenylcarbamoyl,dimethylcarbamoylphenylcarbamoyl, diethylcarbamoylphenylcarbamoyl,N-ethyl-N-methylcarbamoylphenylcarbamoyl,N-isopropyl-N-methylcarbamoylphenylcarbamoyl, etc.], hydroxy (lower)alkylcarbamoyl-arylcarbamoyl [e.g.hydroxymethylcarbamoylphenylcarbamoyl,hydroxyethylcarbamoylphenylcarbamoyl, bis(hydroxyethyl)carbamoylphenylcarbamoyl, etc.],N-[hydroxy(lower)alkyl]-N-(lower alkyl)carbamoyl-arylcarbamoyl [e.g.N-(hydroxyethyl)-N-methylcarbamoylphenylcarbamoyl, etc.], loweralkoxy(lower)alkylcarbamoyl-arylcarbamoyl [e.g.methoxymethylcarbamoylphenylcarbamoyl,methoxyethylcarbamoylphenylcarbamoyl,ethoxyethylcarbamoylphenylcarbamoyl,bis(methoxyethyl)carbamoylphenylcarbamoyl,bis(ethoxyethyl)carbamoylphenylcarbamoyl, etc.], N-[loweralkoxy(lower)alkyl]-N-(lower alkyl)carbamoylarylcarbamoyl [e.g.N-(methoxyethyl)-N-methylcarbamoylphenylcarbamoyl,N-(methoxypropyl)-N-methylcarbamoylphenylcarbamoyl, etc.], loweralkylamino(lower)alkylcarbamoyl-arylcarbamoyl [e.g.methylaminoethylcarbamoylphenylcarbamoyl,dimethylaminoethylcarbamoylphenylcarbamoyl, etc.], N-[loweralkylamino(lower)alkyl]-N-(lower alkyl) carbamoyl-arylcarbamoyl [e.g.N-(dimethylaminoethyl)-N-methyl-carbamoylphenylcarbamoyl,N-(dimethylaminopropyl)-N-methylcarbamoylphenylcarbamoyl, etc.],heterocycliccarbamoylarylcarbamoyl-arylcarbamoyl [e.g.morpholinylcarbamoylphenylcarbamoyl, thienylcarbamoylphenylcarbamoyl,pyridylcarbamoylphenylcarbamoyl, pyrimidinylcarbamoylphenylcarbamoyl,etc.], N-(heterocyclic)-N-(lower alkyl)carbamoyl-arylcarbamoyl [e.g.N-pyridyl-N-methylcarbamoylphenylcarbamoyl, etc.],heterocyclic(lower)alkylcarbamoyl-arylcarbamoyl [e.g.pyridylmethylcarbamoylphenylcarbamoyl,pyridylethylcarbamoylphenylcarbamoyl,thienylmethylcarbamoylphenylcarbamoyl, etc.],N-[heterocyclic(lower)alkyl]-N-(lower alkyl)carbamoyl-arylcarbamoyl[e.g. N-pyridylmethyl-N-methylcarbamoylphenylcarbamoyl, etc.],N-[heterocyclic(lower alkyl]-N-[loweralkoxy(lower)alkyl]-carbamoyl-arylcarbamoyl [e.g.N-pyridylmethyl-N-methoxyethylcarbamoylphenylcarbamoyl,etc.]arylcarbamoyl-arylcarbamoyl [e.g. phenylcarbamoylphenylcarbamoyl,etc.], lower alkylamino-arylcarbamoyl-arylcarbamoyl [e.g.dimethylaminophenylcarbamoylphenylcarbamoyl, etc.], loweralkanoyl-arylcarbamoyl [e.g. acetylphenylcarbamoyl,propionylphenylcarbamoyl, etc.], etc., etc., ar(lower)alkylcarbamoyl[e.g. benzylcarbamoyl, phenethylcarbamoyl, etc.], heterocycliccarbamoyl[e.g. furylcarbamoyl, thienylcarbamoyl, pyridylcarbamoyl,quinolylcarbamoyl, isoquinolylcarbamoyl, pyrimidinylcarbamoyl,pyrazolylcarbamoyl, etc.], heterocyclic(lower)alkylcarbamoyl [e.g.pyridylmethylcarbamoyl, pyridylethylcarbamoyl, furylmethylcarbamoyl,thienylmethylcarbamoyl, etc.], arylaminocarbamoyl [e.g.phenylaminocarbamoyl, etc.], aroylcarbamoyl [e.g. benzoylcarbamoyl,etc.], etc., lower alkylsulfonyl [e.g. mesyl, ethylsulfonyl,propylsulfonyl, isopropylsulfonyl, tert-butylsulfonyl, pentylsulfonyl,etc.], arylsulfonyl [e.g. tosyl, phenylsulfonyl, etc.], ar(lower)alkylsulfonyl [e.g. benzylsulfonyl, phenethylsulfonyl, etc.], ar(lower)alkenylsulfonyl [e.g. styrylsulfonyl, cinnamoylsulfonyl, etc.],phthaloyl, substituted or unsubstituted amino acid residue mentionedbelow, or the like.

Suitable "amino acid residue" may include natural or artificial ones,and such amino acid may be glycine, sarcosine, alanine, β-alanine,valine, norvaline, leucine, isoleucine, norleucine, serine, threonine,cysteine, methionine, phenylalanine, phenylglycine, tryptophan,tyrosine, proline, hydroxyproline, glutamic acid, aspartic acid,glutamine, asparagine, lysine, arginine, histidine, ornithine, or thelike, in which more preferable one is glycine, sarcosine, alanine,β-alanine and proline, and the most preferable one is glycine. And saidamino acid residue may be substituted with suitable substituent(s) suchas the above-mentioned lower alkyl, the above-mentioned aryl, theabove-mentioned acyl, ar(lower)alkyl [e.g. benzyl, phenethyl, trityl,etc.], cycloalkyl [e.g. cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, etc.], a heterocyclicgroup mentioned above, heterocyclic(lower)alkyl [e.g. pyridylmethyl,pyridylethyl, imidazolylmethyl, furylmethyl, thienylmethyl,morpholinomethyl, piperidinomethyl, etc.], substituted or unsubstitutedamidino [e.g. amidino, methylamidino, N-ethyl-N'-cyanoamidino, etc.], orthe like.

Preferred example of said amino acid residue substituted with suitablesubstituent(s) may be amino acid residue substituted with lower alkyl[e.g. ethylglycyl, isopropylglycyl, dimethylglycyl, diethylglycyl,ethylsarcosyl, isopropylsarcosyl, methylalanyl, methyl-β-alanyl,dimethyl-β-alanyl, etc.], amino acid residue substituted with aryl [e.g.N-phenylglycyl, N-tolylglycyl, N-phenylalanyl, N-phenylsarcosyl, etc.],amino acid residue substituted with ar(lower)alkyl [e.g. benzylglycyl,tritylglycyl, phenethylglycyl, benzylsarcosyl, benzylalanyl, etc.],amino acid residue substituted with a heterocyclic group [e.g.morpholinoglycyl, piperidinoglycyl, pyridylglycyl, etc.], amino acidresidue substituted with heterocyclic(lower)alkyl [e.g.pyridylmethylglycyl, imidazolylmethylglycyl, furylmethylglycyl,thienylmethylglycyl, etc.], amino acid residue substituted withcycloalkyl [e.g. cyclopropylglycyl, cyclobutylglycyl, cyclopentylglycyl,cyclohexylglycyl, cycloheptylglycyl, cyclooctylglycyl, adamantylglycyl,cyclohexylsarcosyl, cycloheptylsarcosyl, cyclohexylalanyl, etc.], aminoacid residue substituted with optionally substituted amidino [e.g.amidinoglycyl, methylamidinoglycyl, N-ethyl-N'-cyanoamidinoglycyl,etc.], amino acid residue substituted with acyl such as amino acidresidue substituted with alkanoyl [e.g. formylglycyl, acetylglycyl,acetylsarcosyl, acetylalanyl, acetyl-β-alanyl, propionylglycyl,butyrylglycyl, isobutyrylglycyl, valerylglycyl, isovalerylglycyl,pivaloylglycyl, hexanoylglycyl, heptanoylglycyl, etc.], amino acidresidue substituted with halo(lower)alkanoyl [e.g.trifluoroacetylglycyl, trifluoroacetylsarcosyl, trifluoroacetylalanyl,bromoacetylglycyl, heptafluorobutyrylglycyl, etc.], amino acid residuesubstituted with hydroxy(lower)alkanoyl [e.g. glycoloylglycyl,glycoloylsarcosyl, lactoylglycyl, lactoylalanyl, etc.], amino acidresidue substituted with lower alkylsulfonyloxy(lower)alkanoyl [e.g.mesyloxyacetylglycyl, ethylsulfonyloxyacetylglycyl,mesyloxyacetylsarcosyl, etc.], amino acid residue substituted with loweralkoxy(lower)alkanoyl [e.g. methoxyacetylglycyl, ethoxyacetylglycyl,methoxyacetylsarcosyl, methoxypropionylalanyl, etc.], amino acid residuesubstituted with aryloxy(lower)alkanoyl [e.g. phenyloxyacetylglycyl,phenyloxypropionylglycyl, phenyloxyacetylsarcosyl, etc.], amino acidresidue substituted with lower alkylthio(lower)alkanoyl [e.g.methylthioacetylglycyl, methylthiopropionylglycyl, etc.], amino acidresidue substituted with lower alkylcarbamoyl(lower)alkanoyl [e.g.methylcarbamoylpropionylglycyl, methylcarbamoylpropionylalanyl, etc.],amino acid residue substituted with lower alkanoyloxy(lower)alkanoyl[e.g. acetyloxyacetylglycyl, acetyloxyacetylsarcosyl,propionyloxyacetylglycyl, acetyloxypropionylalanyl, etc.], amino acidresidue substituted with carboxy(lower)alkanoyl [e.g.carboxyacetylglycyl, carboxypropionylglycyl, carboxypropionylsarcosyl,carboxyacetylalanyl, etc.], amino acid residue substituted with loweralkoxycarbonyl(lower)alkanoyl [e.g. methoxycarbonylacetylglycyl,ethoxycarbonylpropionylglycyl, methoxycarbonylacetylsarcosyl, etc.],amino acid residue substituted with ar(lower)alkanoyl [e.g.phenylacetylglycyl, phenylacetylsarcosyl, phenylpropionylalanyl,phenylpropionylglycyl, naphthylacetylglycyl, phenylbutyrylglycyl, etc.],amino acid residue substituted with optionally substitutedheterocyclic(lower)alkanoyl [e.g. morpholinoacetylglycyl,thiomorpholinoacetylglycyl, its oxide or dioxide, pyridylacetylglycyl,morpholinopropionylalanyl, imidazolylacetylglycyl,piperidinoacetylglycyl, pyrrolidinylacetylglycyl,hexamethyleneiminoacetylglycyl, methylpiperazinylacetylglycyl,pyridylpiperazinylacetylglycyl, etc.], amino acid residue substitutedwith lower alkenoyl [e.g. acryloylglycyl, crotonoylglycyl,3-pentenoylglycyl, 3-butenoylglycyl, 4-pentenoylglycyl,3-butenoylsarcosyl, etc.], amino acid residue substituted withsubstituted or unsubstituted ar(lower)alkenoyl, in which said aryl groupmay be substituted with the above-mentioned lower alkyl or lower alkoxy,such as amino acid residue substituted with ar(lower)alkenoyl [e.g.cinnamoylglycyl, allocinnamoylglycyl, α-methylcinnamoylglycyl,4-methylcinnamoylglycyl, cinnamoylsarcosyl, etc.], amino acid residuesubstituted with lower alkoxy-ar(lower)alkenoyl [e.g.methoxycinnamoylglycyl, ethoxycinnamoylglycyl, dimethoxycinnamoylglycyl,etc.], amino acid residue substituted with loweralkylenedioxy-ar(lower)alkenoyl [e.g. methylenedioxycinnamoylglycyl,ethylenedioxycinnamoylglycyl, etc.], amino acid residue substituted withnitro-ar(lower)alkenoyl [e.g. nitrocinnamoylglycyl, etc.], amino acidresidue substituted with cyano-ar(lower)alkenoyl [e.g.cyanocinnamoylglycyl, etc.], amino acid residue substituted withhalo-ar(lower)alkenoyl [e.g. chlorocinnamoylglycyl,fluorocinnamoylglycyl, etc.], amino acid residue substituted withhydroxy-ar(lower)alkenoyl [e.g. hydroxycinnamoylglycyl, etc.], aminoacid residue substituted with hydroxy(lower)alkoxy-ar(lower)alkenoyl[e.g. hydroxymethoxycinnamoylglycyl, hydroxyethoxycinnamoylglycyl,etc.], amino acid residue substituted withamino(lower)alkoxy-ar(lower)alkenoyl [e.g. aminoethoxycinnamoylglycyl,etc.], amino acid residue substituted with loweralkylamino(lower)alkoxy-ar(lower)alkenoyl [e.g.methylaminomethoxycinnamoylglycyl, dimethylaminoethoxycinnamoylglycyl,etc.], amino acid residue substituted withheterocyclic(lower)alkoxy-ar(lower)alkenoyl [e.g.pyridylmethoxycinnamoylglycyl, etc.], amino acid residue substitutedwith optionally substituted heterocyclic-ar(lower)alkenoyl [e.g.morpholinocinnamoylglycyl, methylpiperazinylcinnamoylglycyl,pyrrolidinyl-cinnamoylglycyl, oxopyrrolidinylcinnamoylglycyl,oxopiperidinocinnamoylglycyl, dioxopyrrolidinyl-cinnamoylglycyl,oxooxazolidinylcinnamoylglycyl, pyrrolylcinnamoylglycyl,tetrazolylcinnamoylglycyl, etc.], amino acid residue substituted withheterocyclic(lower)alkyl-ar(lower)alkenoyl [e.g.pyridylmethylcinnamoylglycyl, pyridylethylcinnamoylglycyl,quinolylethylcinnamoylglycyl, etc.], amino acid residue substituted withheterocyclic(lower)alkenyl-ar(lower)alkenoyl [e.g.pyridylvinylcinnamoylglycyl, quinolylvinylcinnamoylglycyl, etc.], aminoacid residue substituted with amino-ar(lower)alkenoyl [e.g.aminocinnamoylglycyl, etc.], amino acid residue substituted with loweralkylamino-ar(lower)alkenoyl [e.g. methylaminocinnamoylglycyl,dimethylaminocinnamoylglycyl, etc.], amino acid residue substituted withacylamino-ar(lower)alkenoyl, for example, amino acid residue substitutedwith lower alkanoylamino-ar(lower)alkenoyl [e.g.acetylaminocinnamoylglycyl, propionylaminocinnamoylglycyl,isobutyrylaminocinnamoyl-glycyl, etc.], amino acid residue substitutedwith cycloalkyl(lower)alkanoylamino-ar(lower)alkenoyl [e.g.cyclopentylacetylaminocinnamoylglycyl,cyclohexylacetylaminocinnamoylglycyl,adamantylacetylaminocinnamoylglycyl, etc.], amino acid residuesubstituted with cycloalkylcarbonylamino-ar(lower)alkenoyl [e.g.cyclopropylcarbonylaminocinnamoylglycyl,cyclopentylcarbonylaminocinnamoylglycyl,cyclohexylcarbonylaminocinnamoylglycyl,adamantylcarbonylaminocinnamoylglycyl, etc.], amino acid residuesubstituted with lower alkenoylamino-ar(lower)alkenoyl [e.g.acryloylaminocinnamoylglycyl, crotonoylaminocinnamoylglycyl, etc.],amino acid residue substituted with loweralkoxycarbonylamino-ar(lower)-alkenoyl [e.g.methoxycarbonylaminocinnamoylglycyl, ethoxycarbonylaminocinnamoylglycyl,etc.], amino acid residue substituted withhydroxy(lower)alkanoylamino-ar(lower)alkenoyl [e.g.hydroxyacetylaminocinnamoylglycyl, hydroxypropionylaminocinnamoylglycyl,etc.], amino acid residue substituted with loweralkoxy(lower)alkanoylamino-ar(lower)alkenoyl [e.g.methoxyacetylaminocinnamoylglycyl, methoxypropionylaminocinnamoylglycyl,etc.], amino acid residue substituted withhalo(lower)alkanoylamino-ar(lower)alkenoyl [e.g.chloroacetylaminocinnamoylglycyl, bromobutyrylaminocinnamoylglycyl,trifluoroacetylaminocinnamoylglycyl, etc.], amino acid residuesubstituted with amino(lower)alkanoylamino-ar(lower)alkenoyl [e.g.aminoacetylaminocinnamoylglycyl, aminopropionylaminocinnamoylglycyl,etc.], amino acid residue substituted with loweralkylamino(lower)alkanoylamino-ar(lower)alkenoyl [e.g.methylaminoacetylaminocinnamoylglycyl,dimethylaminoacetylaminocinnamoylglycyl, etc.], amino acid residuesubstituted with loweralkanoylamino(lower)alkanoylamino-ar(lower)alkenoyl [e.g.acetylaminoacetylaminocinnamoylglycyl,acetylaminopropionylaminocinnamoylglycyl, etc.], amino acid residuesubstituted with carboxy(lower)alkanoylamino-ar(lower)alkenoyl [e.g.carboxyacetylaminocinnamoylglycyl, carboxypropionylaminocinnamoylglycyl,etc.], amino acid residue substituted with loweralkoxycarbonyl(lower)alkanoylamino-ar(lower)alkenoyl [e.g.ethoxycarbonylacetylaminocinnamoylglycyl,ethoxycarbonylpropionylaminocinnamoylglycyl, etc.], amino acid residuesubstituted with loweralkoxycarbonyl(lower)alkenoylamino-ar(lower)alkenoyl [e.g.ethoxycarbonylacryloylaminocinnamoylglycyl, etc.], amino acid residuesubstituted with halo(lower)alkoxycarbonylamino-ar(lower)alkenoyl [e.g.chloroethoxycarbonylaminocinnamoylglycyl, etc.], amino acid residuesubstituted with optionally substitutedheterocyclic(lower)alkanoylamino-ar(lower)alkenoyl [e.g.pyridylacetylaminocinnamoylglycyl, thienylacetylaminocinnamoylglycyl,methylpyrrolylacetylaminocinnamoylglycyl, etc.], amino acid residuesubstituted with aroylamino-ar(lower)alkenoyl [e.g.benzoylaminocinnamoylglycyl, etc.], amino acid residue substituted withoptionally substituted heterocycliccarbonylamino-ar(lower)alkenoyl [e.g.pyridylcarbonylaminocinnamoylglycyl,morpholinocarbonylaminocinnamoylglycyl,furylcarbonylaminocinnamoylglycyl, thienylcarbonylaminocinnamoylglycyl,oxazolylcarbonylaminocinnamoylglycyl,methyloxazolylcarbonylaminocinnamoylglycyl,dimethylisoxazolylcarbonylaminocinnamoylglycyl,imidazolylcarbonylaminocinnamoylglycyl,methylimidazolylcarbonylaminocinnamoylglycyl,piperidylcarbonylaminocinnamoylglycyl,ethylpiperidylcarbonylaminocinnamoylglycyl,acetylpiperidylcarbonylaminocinnamoylglycyl,pyrrolidinylcarbonylaminocinnamoylglycyl,acetylpyrrolidinylcarbonylaminocinnamoylglycyl,tert-butoxycarbonylpyrrolidinylcarbonylaminocinnamoylglycyl, etc.],amino acid residue substituted with loweralkylsulfonylamino-ar(lower)alkenoyl [e.g. mesylaminocinnamoylglycyl,ethylsulfonylaminocinnamoylglycyl, etc.], etc., amino acid residuesubstituted with N-(lower alkanoyl)-N-(loweralkyl)amino-ar(lower)alkenoyl [e.g.N-acetyl-N-methylaminocinnamoylglycyl,N-acetyl-N-ethylaminocinnamoylglycyl,N-propionyl-N-methylaminocinnamoylglycyl, etc.], amino acid resieuesubstituted with N-[lower alkoxy(lower)alkanoyl]-N-(loweralkyl)amino-ar(lower)alkenoyl [e.g.N-methoxyacetyl-N-methylaminocinnamoylglycyl,N-methoxypropionyl-N-methylaminocinnamoylglycyl, etc.], amino acidresidue substituted with N-(loweralkanoyl)-N-[heterocyclic(lower)alkyl]amino-ar(lower)alkenoyl [e.g.N-acetyl-N-pyridylmethylaminocinnamoylglycyl, etc.], amino acid residuesubstituted with N-(lower alkanoyl)-N-[loweralkoxy(lower)alkyl]amino-ar(lower)alkenoyl [e.g.N-acetyl-N-methoxyethylaminocinnamoylglycyl,N-acetyl-N-methoxymethylaminocinnamoylglycyl,N-propianyl-N-methoxyethylaminocinnamoylglycyl, etc.], amino acidresidue substituted with N-(lower alkanoyl)-N-[loweralkoxycarbonyl(lower)alkyl]amino-ar(lower)alkenoyl [e.g.N-acetyl-N-tert-butoxycarbonylmethylaminocinnamoylglycyl,N-acetyl-N-tert-butoxycarbonylethylaminocinnamoylglycyl,N-propionyl-N-tert-butoxycarbonylmethylaminocinnamoylglycyl, etc.],amino acid residue substituted with N-(loweralkanoyl)-N-[carboxy(lower)alkyl]amino-ar(lower)-alkenoyl [e.g.N-acetyl-N-carboxymethylaminocinnamoylglycyl,N-acetyl-N-carboxyethylaminocinnamoylglycyl,N-propionyl-N-carboxymethylaminocinnamoylglycyl, etc.], amino acidresidue substituted with N-[loweralkoxy(lower)alkanoyl]-N-[heterocyclic(lower)alkyl]amino-ar(lower)alkenoyl[e.g. N-methoxyacetyl-N-pyridylmethylaminocinnamoylglycyl,N-methoxypropionyl-N-pyridylmethylaminocinnamoylglycyl, etc.], aminoacid residue substituted with N-[heterocycliccarbonyl]-N-[loweralkoxy(lower)alkyl]amino-ar(lower)alkenoyl [e.g.N-pyridylcarbonyl-N-methoxymethylaminocinnamoylglycyl,N-pyridylcarbonyl-N-methoxyethylaminocinnamoylglycyl,N-thienylcarbonyl-N-methoxyethylaminocinnamoylglycyl, etc.], amino acidresidue substituted with ureido-ar(lower)alkenoyl [e.g.ureidocinnamoylglycyl, etc.], amino acid residue substituted with loweralkylureido-ar(lower)alkenoyl [e.g. methylureidocinnamoylglycyl,ethylureidocinnamoylglycyl, dimethylureidocinnamoylglycyl, etc.], aminoacid residue substituted with heterocyclicureido-ar(lower)alkenoyl,[e.g. pyridylureidocinnamoylglycyl, pyrimidinylureidocinnamoylglycyl,thienylureidocinnamoylglycyl, etc.], amino acid residue substituted withacyl-ar(lower)alkenoyl, for example, amino acid residue substituted withlower alkanoyl-ar(lower)alkenoyl [e.g. formylcinnamoylglycyl,acetylcinnamoylglycyl, propionylcinnamoylglycyl, etc.], amino acidresidue substituted with carboxy-ar(lower)-alkenoyl [e.g.carboxycinnamoylglycyl, etc.], amino acid residue substituted with loweralkoxycarbonyl-ar(lower)alkenoyl [e.g. methoxycarbonylcinnamoylglycyl,ethoxycarbonylcinnamoylglycyl, etc.], amino acid residue substitutedwith carbamoyl-ar(lower)-alkenoyl [e.g. carbamoylcinnamoylglycyl, etc.],amino acid residue substituted with loweralkylcarbamoyl-ar(lower)alkenoyl [e.g. methylcarbamoylcinnamoylglycyl,ethylcarbamoylcinnamoylglycyl, dimethylcarbamoylcinnamoylglycyl,propylcarbamoylcinnamoylglycyl, isopropylcarbamoylcinnamoylglycyl,diethylcarbamoylcinnamoylglycyl,N-methyl-N-ethylcarbamoylcinnamoylglycyl, etc.], amino acid residuesubstituted with hydroxy(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.hydroxyethylcarbamoylcinnamoylglycyl,bis(hydroxyethyl)carbamoylcinnamoylglycyl, etc.], amino acid residuesubstituted with N-[hydroxy(lower)alkyl]-N-(loweralkyl)carbamoyl-ar(lower)alkenoyl [e.g.N-hydroxyethyl-N-methylcarbamoylcinnamoylglycyl, etc.], amino acidresidue substituted with loweralkoxy(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.methoxymethylcarbamoylcinnamoylglycyl,methoxyethylcarbamoylcinnamoylglycyl,bis(methoxyethyl)-carbamoylcinnamoylglycyl,ethoxyethylcarbamoylcinnamoylglycyl,methoxypropylcarbamoylcinnamoylglycyl,bis(ethoxyethyl)carbamoylcinnamoylglycyl, etc.], amino acid residuesubstituted with N-[lower alkoxy(lower)alkyl]-N-(loweralkyl)carbamoyl-ar(lower)-alkenoyl [e.g.N-methoxyethyl-N-methylcarbamoylcinnamoylglycyl,N-ethoxyethyl-N-methylcarbamoylcinnamoylglycyl, etc.], amino acidresidue substituted withheterocyclic(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.pyridylmethylcarbamoylcinnamoylglycyl,furylmethylcarbamoylcinnamoylglycyl,thienylmethylcarbamoylcinnamoylglycyl, etc.], amino acid residuesubstituted with N-[heterocyclic(lower)alkyl]-N-(loweralkyl)carbamoyl-ar(lower)alkenoyl [e.g.N-pyridylmethyl-N-methylcarbamoylcinnamoylglycyl, etc.], amino acidresidue substituted with heterocycliccarbamoyl-ar(lower)alkenoyl [e.g.morpholinylcarbamoylcinnamoylglycyl, thienylcarbamoylcinnamoylglycyl,pyridylcarbamoylcinnamoylglycyl, pyrimidinylcarbamoyl-cinnamoylglycyl,tetrazolylcarbamoylcinnamoylglycyl, etc.], amino acid residuesubstituted with optionally substitutedheterocycliccarbonyl-ar(lower)alkenoyl [e.g.morpholinocarbonylcinnamoylglycyl, pyrrolidinyl-carbonylcinnamoylglycyl,piperidinocarbonylcinnamoylglycyl,tetrahydropyridylcarbonylcinnamoylglycyl,methylpiperazinylcarbonylcinnamoylglycyl, etc.], amino acid residuesubstituted with lower alkenylcarbamoyl-ar (lower)alkenoyl [e.g.vinylcarbamoylcinnamoylglycyl, allylcarbamoylcinnamoylglycyl,methylpropenylcarbamoylcinnamoylglycyl, etc.], amino acid residuesubstituted with lower alkynylcarbamoyl-ar(lower)alkenoyl [e.g.ethynylcarbamoylcinnamoylglycyl, propynylcarbamoylcinnamoylglycyl,etc.], amino acid residue substituted withamino(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.aminomethylcarbamoylcinnamoylglycyl, aminoethylcarbamoylcinnamoylglycyl,etc.], amino acid residue substituted with loweralkylamino(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.methylaminomethylcarbamoylcinnamoylglycyl,methylaminoethylcarbamoylcinnamoylglycyl,ethylaminoethylcarbamoylcinnamoylglycyl,dimethylaminoethylcarbamoylcinnamoylglycyl, etc.], amino acid residuesubstituted with loweralkylcarbamoyloxy(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.methylcarbamoyloxymethylcarbamoylcinnamoylglycyl,methylcarbamoyloxyethylcarbamoylcinnamoylglycyl,ethylcarbamoyloxyethylcarbamoylcinnamoylglycyl,dimethylcarbamoyloxyethylcarbamoylcinnamoylglycyl, etc.], amino acidresidue substituted with loweralkylcarbamoyl(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.methylcarbamoylmethylcarbamoylcinnamoylglycyl,methylcarbamoylethylcarbamoylcinnamoylglycyl,ethylcarbamoylethylcarbamoylcinnamoylglycyl,dimethylcarbamoylethylcarbamoylcinnamoylglycyl, etc.], amino acidresidue substituted with loweralkoxycarbonyl(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.methoxycarbonylmethylcarbamoylcinnamoylglycyl,methoxycarbonylethylcarbamoylcinnamoylglycyl,ethoxycarbonylmethylcarbamoylcinnamoylglycyl,ethoxycarbonylethylcarbamoylcinnamoylglycyl, etc.], amino acid residuesubstituted with carboxy(lower)alkylcarbamoyl-ar(lower)alkenoyl [e.g.carboxymethylcarbamoylcinnamoylglycyl,carboxyethylcarbamoylcinnamoylglycyl, etc.], amino acid residuesubstituted with [loweralkylcarbamoyl-ar(lower)alkyl]carbamoyl-ar(lower)alkenoyl [e.g.(methylcarbamoyl-phenethyl)carbamoylcinnamoylglycyl,(ethylcarbamoyl-phenethyl)carbamoylcinnamoylglycyl, etc.], amino acidresidue substituted with [loweralkoxycarbonyl-ar(lower)alkyl]carbamoyl-ar(lower)alkenoyl [e.g.(methoxycarbonyl-phenethyl)carbamoylcinnamoylglycyl,(ethoxycarbonyl-phenethyl)carbamoylcinnamoylglycyl, etc.], amino acidresidue substituted with[carboxy-ar(lower)alkyl]carbamoyl-ar(lower)alkenoyl [e.g.(carboxy-phenethyl)carbamoylcinnamoylglycyl, etc.], amino acid residuesubstituted with N-[lower alkylcarbamoyl(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl [e.g.N-(methyl-carbamoylmethyl)-N-methylcarbamoylcinnamoylglycyl,N-(methylcarbamoylethyl)-N-methylcarbamoylcinnamoylglycyl,N-(ethylcarbamoylethyl)-N-methylcarbamoylcinnamoylglycyl,N-(dimethylcarbamoylethyl)-N-methylcarbamoylcinnamoylglycyl, etc.],amino acid residue substituted with N-[loweralkoxycarbonyl(lower)alkyl]-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl[e.g. N-methoxycarbonylmethyl-N-methylcarbamoylcinnamoylglycyl,N-methoxycarbonylethyl-N-methylcarbamoylcinnamoylglycyl,N-ethoxycarbonylmethyl-N-methylcarbamoylcinnamoylglycyl,N-ethoxycarbonylethyl-N-methylcarbamoylcinnamoylglycyl, etc.], aminoacid residue substituted with N-[carboxy(lower)alkyl]-N-(loweralkyl)carbamoyl-ar(lower)alkenoyl [e.g.N-carboxymethyl-N-methylcarbamoylcinnamoylglycyl,N-carboxyethyl-N-methylcarbamoylcinnamoylglycyl, etc.], amino acidresidue substituted with arylcarbamoyl-ar(lower)alkenoyl [e.g.phenylcarbamoylcinnamoylglycyl, naphthylcarbamoylcinnamoylglycyl, etc.],etc., etc., amino acid residue substituted with ar(lower)alkynoyl [e.g.phenylpropioloylglycyl, etc.], amino acid residue substituted withsubstituted or unsubstituted heterocyclic(lower)alkenoyl, in which saidheterocyclic group may be substituted with the above-mentioned loweralkyl or lower alkoxy, such as amino acid residue substituted withheterocyclic(lower)alkenoyl [e.g. morpholinylacryloylglycyl,pyridylacryloylglycyl, thienylacryloylglycyl, etc.], amino acid residuesubstituted with heterocyclic(lower)alkyl-heterocyclic(lower)alkenoyl[e.g. pyridylmethylpyridylacryloylglycyl,pyridylethylpyridylacryloylglycyl, quinolylethylpyridylacryloylglycyl,etc.], amino acid residue substituted withheterocyclic(lower)alkenyl-heterocyclic(lower)alkenoyl [e.g.pyridylvinylpyridylacryloylglycyl, quinolylvinylpyridylacryloylglycyl,etc.], amino acid residue substituted withamino-heterocyclic(lower)alkenoyl [e.g. aminopyridylacryloylglycyl,etc.], amino acid residue substituted with loweralkylamino-heterocyclic(lower)alkenoyl [e.g.methylaminopyridylacryloylglycyl, dimethylaminopyridylacryloylglycyl,etc.], amino acid residue substituted withacylamino-heterocyclic(lower)alkenoyl, for example, amino acid residuesubstituted with lower alkanoylamino-heterocyclic(lower)alkenoyl [e.g.acetylaminopyridylacryloylglycyl, propionylaminopyridylacryloylglycyl,etc.], amino acid residue substituted with loweralkenoylamino-heterocyclic(lower)alkenoyl [e.g.acryloylaminopyridylacryloylglycyl, crotonoylaminopyridylacryloylglycyl,etc.], amino acid residue substituted withheterocyclic(lower)alkanoylamino-heterocyclic (lower)-alkenoyl [e.g.pyridylacetylaminopyridylacryloylglycyl,thienylacetylaminopyridylacryloylglycyl, etc.], amino acid residuesubstituted with heterocycliccarbonylamino-heterocyclic(lower)alkenoylwhich may be substituted with lower alkyl [e.g.pyridylcarbonylaminopyridylacryloylglycyl,furylcarbonylaminopyridylacryloylglycyl,methylpyridylcarbonylaminopyridylacryloylglycyl, etc.], amino acidresidue substituted with lower alkanoylamino-(lower)alkanoylamino-heterocyclic(lower)alkenoyl [e.g.acetylaminoacetylaminopyridylacryloylglycyl,acetylaminopropionylaminopyridylacryloylglycyl, etc.], amino acidresidue substituted with lower alkoxycarbonyl-(lower)alkanoylamino-heterocyclic(lower)alkenoyl [e.g.ethoxycarbonylacetylaminopyridylacryloylglycyl,ethoxycarbonylpropionylaminopyridylacryloylglycyl, etc.], amino acidresidue substituted with loweralkoxy(lower)alkanoylamino-heterocyclic(lower)alkenoyl [e.g.methoxyacetylaminopyridylacryloylglycyl,methoxypropionylaminopyridylacryloylglycyl,ethoxypropionylaminopyridylacryloylglycyl, etc.], etc., amino acidresidue substituted with lower alkylureido-heterocyclic(lower)alkenoyl[e.g. methylureidopyridylacryloylglycyl, etc.], amino acid residuesubstituted with acyl-heterocyclic(lower)alkenoyl, for example, aminoacid residue substituted with carboxy-heterocyclic(lower)alkenoyl [e.g.carboxypyridylacryloylglycyl, etc.], amino acid residue substituted withlower alkoxycarbonyl-heterocyclic(lower)alkenoyl [e.g.ethoxycarbonylpyridylacryloylglycyl, etc.], amino acid residuesubstituted with lower alkanoyl-heterocyclic(lower)alkenoyl [e.g.acetylpyridylacryloylglycyl, acetyltetrahydroquinolylacryloylglycyl,etc.], amino acid residue substituted with loweralkylcarbamoyl-heterocyclic(lower)alkenoyl [e.g.methylcarbamoylpyridylacryloylglycyl,ethylcarbamoylpyridylacryloylglycyl,dimethylcarbamoylpyridylacryloylglycyl,diethylcarbamoylpyridylacryloylglycyl,isopropylcarbamoylpyridylacryloylglycyl,N-ethyl-N-methylcarbamoylpyridylacryloylglycyl, etc.], amino acidresidue substituted with loweralkoxy(lower)alkylcarbamoyl-heterocyclic(lower)alkenoyl [e.g.methoxymethylcarbamoylpyridylacryloylglycyl,methoxyethylcarbamoylpyridylacryloylglycyl,methoxypropylcarbamoylpyridylacryloylglycyl,ethoxyethylcarbamoylpyridylacryloylglycyl, bis(methoxy-ethyl)carbamoylpyridylacryloylglycyl, etc.], amino acid residue substitutedwith hydroxy(lower)alkylcarbamoyl-heterocyclic(lower)alkenoyl [e.g.hydroxymethylcarbamoylpyridylacryloylglycyl,hydroxyethylcarbamoylpyridylacryloylglycyl, bis(hydroxy-ethyl)carbamoylpyridylacryloylglycyl, etc.], amino acid residue substitutedwith heterocycliccarbamoyl-heterocyclic(lower)alkenoyl [e.g.pyridylcarbamoylpyridylacryloylglycyl,morpholinylcarbamoylpyridylacryloylglycyl,thienylcarbamoylpyridylacryloylglycyl,pyrimidinylcarbamoylpyridylacryloylglycyl, etc.], amino acid residuesubstituted with heterocyclic-(lower)alkylcarbamoyl-heterocyclic(lower)alkenoyl [e.g.pyridylmethylcarbamoylpyridylacryloylglycyl,furylmethylcarbamoylpyridylacryloylglycyl,thienylmethylcarbamoylpyridylacryloylglycyl, etc.], amino acid residuesubstituted with heterocycliccarbonyl-heterocyclic (lower)alkenoyl [e.g.morpholinocarbonylpyridylacryloylglycyl,pyrrolidinylcarbonylpyridylacryloylglycyl,piperidinocarbonylpyridylacryloylglycyl, etc.], amino acid residuesubstituted with lower alkenylcarbamoyl-heterocyclic(lower)alkenoyl[e.g. vinylcarbamoylpyridylacryloylglycyl,allylcarbamoylpyridylacryloylglycyl, etc.], amino acid residuesubstituted with lower alkynylcarbamoyl-heterocyclic(lower)alkenoyl[e.g. ethynylcarbamoylpyridylacryloylglycyl,propynylcarbamoylpyridylacryloylglycyl, etc.], etc., etc., amino acidresidue substituted with heterocyclicthio(lower)alkanoyl [e.g.pyridylthioacetylglycyl, pyrimidinylthioacetylglycyl,imidazolylthiopropionylglycyl, etc.], amino acid residue substitutedwith optionally substituted heterocycliccarbonyl [e.g.morpholinocarbonylglycyl, indolylcarbonylglycyl,4-methyl-1-piperazinylcarbonylglycyl, etc.], amino acid residuesubstituted with cyclo(lower)alkylcarbonyl [e.g.cyclopropylcarbonylglycyl, cyclopentylcarbonylglycyl,cyclohexylcarbonylglycyl, cyclohexylcarbonylsarcosyl, etc.], amino acidresidue substituted with lower alkoxycarbonyl [e.g.methoxycarbonylglycyl, tert-butoxycarbonylglycyl,tert-butoxycarbonylsarcosyl, tert-butoxycarbonylalanyl, etc.], aminoacid residue substituted with aryloxycarbonyl [e.g.phenoxycarbonylglycyl, etc.], amino acid residue substituted witharoyl(lower)alkanoyl [e.g. phenyloxalylglycyl, benzoylpropionylglycyl,etc.], amino acid residue substituted with aroyl [e.g. benzoylglycyl,naphthoylglycyl, benzoylsarcosyl, benzoylalanyl, etc.], amino acidresidue substituted with nitro-aryloxycarbonyl [e.g.nitrophenyloxycarbonylglycyl, etc.], amino acid residue substituted withcarbamoyl [e.g. carbamoylglycyl, carbamoylalanyl, carbamoylsarcosyl,carbamoyl-β-alanyl, etc.], amino acid residue substituted with loweralkylcarbamoyl [e.g. methylcarbamoylglycyl, ethylcarbamoylglycyl,propylcarbamoylglycyl, isopropylcarbamoylglycyl,methylcarbamoylsarcosyl, ethylcarbamoylalanyl,isopropylcarbamoyl-β-alanyl, pentylcarbamoylglycyl, etc.], amino acidresidue substituted with lower alkoxycarbonyl(lower)alkylcarbamoyl [e.g.methoxycarbonylmethylcarbamoylglycyl,ethoxycarbonylmethylcarbamoylglycyl, etc.], amino acid residuesubstituted with lower alkenylcarbamoyl [e.g. vinylcarbamoylglycyl,allylcarbamoylglycyl, allylcarbamoylsarcosyl, etc.], amino acid residuesubstituted with cyclo(lower)alkylcarbamoyl [e.g.cyclopropylcarbamoylglycyl, cyclohexylcarbamoylglycyl,cyclohexylcarbamoylsarcosyl, etc.], amino acid residue substituted witharylcarbamoyl [e.g. phenylcarbamoylglycyl, naphthylcarbamoylglycyl,tolylcarbamoylglycyl, ethylphenylcarbamoylglycyl, phenylcarbamoylalanyl,phenylcarbamoylsarcosyl, etc.], amino acid residue substituted withlower alkoxy-arylcarbamoyl [e.g. methoxyphenylcarbamoylglycyl,ethoxyphenylcarbamoylglycyl, methoxyphenylcarbamoylalanyl, etc.], aminoacid residue substituted with halo(lower)alkyl-arylcarbamoyl [e.g.triluoromethylphenylcarbamoylglycyl,trifluoromethylphenylcarbamoylalanyl,trifluoromethylphenylcarbamoylsarcosyl, etc.], amino acid residuesubstituted with halo-arylcarbamoyl [e.g. chlorophenylcarbamoylglycyl,fluorophenylcarbamoylglycyl, fluorophenylcarbamoylalanyl, etc.], aminoacid residue substituted with hydroxy(lower)alkyl-arylcarbamoyl [e.g.hydroxymethylphenylcarbamoylglycyl, hydroxyethylphenylcarbamoylglycyl,hydroxyethylphenylcarbamoylalanyl, etc.], amino acid residue substitutedwith nitro-arylcarbamoyl [e.g. nitrophenylcarbamoylglycyl, etc.], aminoacid residue substituted with cyano-arylcarbamoyl [e.g.cyanophenylcarbamoylglycyl, etc.], amino acid residue substituted withamino-arylcarbamoyl [e.g. aminophenylcarbamoylglycyl, etc.], amino acidresidue substituted with lower alkylamino-arylcarbamoyl [e.g.methylaminophenylcarbamoylglycyl, ethylaminophenylcarbamoylglycyl,dimethylaminophenylcarbamoylglycyl, etc.], amino acid residuesubstituted with lower alkanoylamino-arylcarbamoyl [e.g.acetylaminophenylcarbamoylglycyl, propionylaminophenylcarbamoylglycyl,etc.], amino acid residue substituted with N-(lower alkanoyl)-N-(loweralkyl)amino-arylcarbamoyl [e.g.N-acetyl-N-methylaminophenylcarbamoylglycyl,N-propionyl-N-methylaminophenylcarbamoylglycyl, etc.], amino acidresidue substituted with lower alkoxy(lower)alkanoylamino-arylcarbamoyl[e.g. methoxyacetylaminophenylcarbamoylglycyl,methoxypropionylaminophenylcarbamoylglycyl, etc.], amino acid residuesubstituted with lower alkoxycarbonyl(lower)alkanoylamino-arylcarbamoyl[e.g. ethoxycarbonylacetylaminophenylcarbamoylglycyl,methoxycarbonylpropionylaminophenylcarbamoylglycyl, etc.], amino acidresidue substituted with carboxyamino-arylcarbamoyl [e.g.carboxyaminophenylcarbamoylglycyl, etc.], amino acid residue substitutedwith lower alkoxycarbonylamino-arylcarbamoyl [e.g.ethoxycarbonylaminophenyl-carbamoylglycyl, etc.], amino acid residuesubstituted with aroylamino-arylcarbamoyl [e.g.benzoylaminophenylcarbamoylglycyl, etc.], amino acid residue substitutedwith heterocycliccarbonylamino-arylcarbamoyl [e.g.pyridylcarbonylaminophenylcarbamoylglycyl,furylcarbonylaminophenylcarbamoylglycyl,morpholinocarbonylaminophenylcarbamoylglycyl, etc.], amino acid residuesubstituted with heterocyclic(lower)alkanoylamino-arylcarbamoyl [e.g.pyridylacetylaminophenylcarbamoylglycyl,thienylacetylaminophenylcarbamoylglycyl, etc.], amino acid residuesubstituted with ureido-arylcarbamoyl [e.g. ureidophenylcarbamoylglycyl,etc.], amino acid residue substituted with loweralkylureido-arylcarbamoyl [e.g. methylureidophenylcarbamoylglycyl,ethylureidophenylcarbamoylglycyl, etc.], amino acid residue substitutedwith hydroxyimino(lower)alkyl-arylcarbamoyl [e.g.hydroxyiminoethylphenylcarbamoylglycyl, etc.], amino acid residuesubstituted with lower alkoxyimino(lower)alkyl-arylcarbamoyl [e.g.methoxyiminoethylphenylcarbamoylglycyl, etc.], amino acid residuesubstituted with lower alkylhydrazono(lower)alkyl-arylcarbamoyl [e.g.methylhydrazonoethylphenylcarbamoylglycyl,dimethylhydrazonoethylphenylcarbamoylglycyl, etc.], amino acid residuesubstituted with optionally substituted heterocyclic-arylcarbamoyl [e.g.oxopyrrolidinylphenylcarbamoylglycyl,oxopiperidinophenylcarbamoylglycyl,dioxopyrrolidinylphenylcarbamoylglycyl,oxooxazolidinylphenylcarbamoylglycyl, pyrrolylphenylcarbamoylglycyl,etc.], amino acid residue substituted with acyl-arylcarbamoyl, forexample, amino acid residue substituted with loweralkanoyl-arylcarbamoyl [e.g. acetylphenylcarbamoylglycyl,propionylphenylcarbamoylglycyl, etc.], amino acid residue substitutedwith heterocycliccarbonyl-arylcarbamoyl [e.g.morpholinocarbonylphenylcarbamoylglycyl,piperidinocarbonylphenylcarbamoylglycyl,piperazinylcarbonylphenylcarbamoylglycyl,thiomorpholinocarbonylphenylcarbamoylalanyl,pyrrolidinylcarbonylphenylcarbamoylglycyl,1,2,3,6-tetrahydropyridylcarbonylphenylcarbamoylglycyl, etc.], aminoacid residue substituted with carboxy-arylcarbamoyl [e.g.carboxyphenylcarbamoylglycyl, etc.], amino acid residue substituted withlower alkoxycarbonyl-arylcarbamoyl [e.g.methoxycarbonylphenylcarbamoylglycyl,ethoxycarbonyl-phenylcarbamoylglycyl, etc.], amino acid residuesubstituted with carbamoyl-arylcarbamoyl [e.g.carbamoylphenylcarbamoylglycyl, etc.], amino acid residue substitutedwith lower alkylcarbamoyl-arylcarbamoyl [e.g.methylcarbamoylphenylcarbamoylglycyl,ethylcarbamoylphenylcarbamoylglycyl,propylcarbamoylphenylcarbamoylglycyl,dimethylcarbamoylphenylcarbamoylglycyl,diethylcarbamoylphenylcarbamoylglycyl,N-ethyl-N-methylcarbamoylphenylcarbamoylglycyl,N-isopropyl-N-methylcarbamoylphenylcarbamoylglycyl, etc.], amino acidresidue substituted with heterocycliccarbonyl-arylcarbamoyl having loweralkyl [e.g. methylpiperazinylcarbonylphenylcarbamoylglycyl,ethylpiperazinylcarbonylphenylcarbamoylglycyl, etc.], amino acid residuesubstituted with heterocycliccarbonyl-arylcarbamoyl having aryl [e.g.phenylpiperazinylcarbonylphenylcarbamoylglycyl, etc.], amino acidresidue substituted with heterocycliccarbonyl-arylcarbamoyl having aheterocyclic group [e.g.pyridylpiperazinylcarbonylphenylcarbamoylglycyl, etc.], amino acidresidue substituted with heterocycliccarbonyl-arylcarbamoyl having loweralkanoyl [e.g. acetylpiperazinylcarbonylphenylcarbamoylglycyl, etc.],amino acid residue substituted with heterocycliccarbonyl-arylcarbamoylhaving lower alkoxycarbonyl [e.g.ethoxycarbonylpiperazinylcarbonyl-phenylcarbamoylglycyl, etc.], aminoacid residue substituted with heterocycliccarbonyl-arylcarbamoyl havinglower alkylamino [e.g.methylaminopiperazinylcarbonyl-phenylcarbamoylglycyl,dimethylaminopiperidinocarbonyl-phenylcarbamoylglycyl, etc.], amino acidresidue substituted with heterocycliccarbonyl-arylcarbamoyl having loweralkylcarbamoyl [e.g.methyl-carbamoylpiperazinylcarbonylphenylcarbamoylglycyl, etc.], aminoacid residue substituted with hydroxy(lower)alkylcarbamoyl-arylcarbamoyl[e.g. hydroxymethylcarbamoylphenylcarbamoylglycyl,hydroxyethylcarbamoylphenylcarbamoylglycyl,bis(hydroxyethyl)carbamoylphenylcarbamoylglycyl, etc.], amino acidresidue substituted with N-[hydroxy(lower) alkyl]-N-(loweralkyl)carbamoyl-arylcarbamoyl [e.g.N-(hydroxyethyl)-N-methylcarbamoyl-phenylcarbamoylglycyl, etc.], aminoacid residue substituted with loweralkoxy(lower)alkylcarbamoyl-aryl-carbamoyl [e.g.methoxymethylcarbamoylphenylcarbamoylglycyl,methoxyethylcarbamoylphenylcarbamoylglycyl,methoxyethylcarbamoylphenylcarbamoylglycyl,bis(methoxyethyl)carbamoylphenylcarbamoylglycyl,bis(ethoxyethyl)carbamoylphenylcarbamoylglycyl, etc.], amino acidresidue substituted with N-[lower alkoxy-(lower) alkyl]-N-(loweralkyl)carbamoyl-arylcarbamoyl [e.g.N-(methoxyethyl)-N-methylcarbamoylphenylcarbamoylglycyl,N-(methoxypropyl)-N-methylcarbamoylphenylcarbamoylglycyl, etc.], aminoacid residue substituted with lower alkylamino (lower)alkylcarbamoyl-arylcarbamoyl [e.g.methylaminoethylcarbamoylphenylcarbamoylglycyl,dimethylaminoethylcarbamoylphenylcarbamoylglycyl, etc.], amino acidresidue substituted with N-[lower alkylamino(lower)alkyl-N-(loweralkyl)carbamoyl-arylcarbamoyl [e.g.N-(dimethyaminoethyl)-N-methylcarbamoylphenylcarbamoylglycyl,N-(dimethylaminopropyl)-N-methylcarbamoylphenylcarbamoylglycyl, etc.],amino acid residue substituted with heterocycliccarbamoyl-arylcarbamoyl[e.g. morpholinylcarbamoylphenylcarbamoylglycyl,thienylcarbamoylphenylcarbamoylglycyl,pyridylcarbamoylphenylcarbamoylglycyl,pyrimidinylcarbamoylphenylcarbamoylglycyl, etc.], amino acid residuesubstituted with N-(heterocyclic)-N-(lower alkyl)carbamoyl-arylcarbamoyl[e.g. N-pyridyl-N-methylcarbamoylphenylcarbamoylglycyl, etc.], aminoacid residue substituted withheterocyclic(lower)alkylcarbamoyl-arylcarbamoyl [e.g.pyridylmethylcarbamoylphenylcarbamoylglycyl,pyridylethylcarbamoylphenylcarbamoylglycyl,thienylmethylcarbamoylphenylcarbamoylglycyl, etc.], amino acid residuesubstituted with N-[heterocyclic(lower)alkyl]-N-(loweralkyl)carbamoyl-arylcarbamoyl [e.g.N-pyridylmethyl-N-methylcarbamoyl-phenylcarbamoylglycyl, etc.], aminoacid residue substituted with N-[heterocyclic(lower)alkyl]-N-[loweralkoxy(lower)alkyl]-carbamoyl-arylcarbamoyl [e.g.N-pyridylmethyl-N-methoxyethylcarbamoylphenylcarbamoylglycyl, etc.],amino acid residue substituted with arylcarbamoyl-arylcarbamoyl [e.g.phenylcarbamoylphenylcarbamoylglycyl, etc.], amino acid residuesubstituted with lower alkylaminoarylcarbamoyl-arylcarbamoyl [e.g.dimethylamino-phenylcarbamoylphenylcarbamoylglycyl, etc.], etc., aminoacid residue substituted with arylthiocarbamoyl [e.g.phenylthiocarbamoylglycyl, naphthylthiocarbamoylglycyl,phenylthiocarbamoylalanyl, phenylthiocarbamoylsarcosyl, etc.], aminoacid residue substituted with ar(lower)alkylcarbamoyl [e.g.benzylcarbamoylglycyl, benzylcarbamoylsarcosyl, benzylcarbamoylalanyl,etc.], amino acid residue substituted with aroylcarbamoyl [e.g.benzoylcarbamoylglycyl, etc.], amino acid residue substituted withheterocycliccarbamoyl [e.g. pyridylcarbamoylglycyl,pyridylcarbamoylalanyl, pyridylcarbamoylsarcosyl,thienylcarbamoylglycyl, pyrazolylcarbamoylglycyl,pyrimidinylcarbamoylglycyl, quinolylcarbamoylglycyl,isoquinolylcarbamoylglycyl, etc.], amino acid residue substituted withheterocyclic(lower)alkylcarbamoyl [e.g. pyridylmethylcarbamoylglycyl,pyridylethylcarbamoylglycyl, thienylmethylcarbamoylglycyl, etc.], aminoacid residue substituted with arylaminocarbamoyl [e.g.phenylaminocarbamoylglycyl, etc.], amino acid residue substituted withar(lower)alkenylsulfonyl [e.g. styrylsulfonylglycyl,cinnamylsulfonylglycyl, etc.], amino acid residue substituted with loweralkylsulfonyl [e.g. mesylglycyl, ethylsulfonylglycyl, mesylsarcosyl,mesylalanyl, etc.], amino acid residue substituted with phthaloyl [e.g.phthaloylglycyl, phthaloylalanyl, phthaloyl-β-alanyl, etc.], amino acidresidue having unsubstituted amino acid residue [e.g. glycylglycyl,alanylglycyl, sarcosylglycyl, prolylglycyl, glycylsarcosyl,prolylsarcosyl, etc.], amino acid residue having substituted amino acidresidue [e.g. amino acid residue having amino acid residue substitutedwith lower alkyl (e.g. dimethylglycylglycyl, diethylglycylglycyl,dimethylglycylsarcosyl, ethylsarcosylglycyl, isopropylsarcosylglycyl,ethylglycylglycyl, propylglycylglycyl, isopropylglycylglycyl,ethylglycylalanyl, dimethylglycylalanyl, dimethylalanylglycyl,dimethyl-β-alanylglycyl, etc.), amino acid residue having amino acidresidue substituted with a heterocyclic group (e.g.morpholinoglycylglycyl, piperidinoglycylglycyl, pyridylglycylglycyl,piperidinosarcosylglycyl, etc.), amino acid residue having amino acidresidue substituted with heterocyclic(lower)alkyl (e.g.pyridylmethylglycylglycyl, imidazolylmethylglycylglycyl,furylmethylglycylglycyl, thienylmethylsarcosylglycyl, etc.), amino acidresidue having amino acid residue substituted with cycloalkyl (e.g.cyclopropylglycylglycyl, cyclobutylglycylglycyl,cyclopentylglycylglycyl, cyclohexylglycylglycyl,cycloheptylglycylglycyl, cyclooctylglycylglycyl, adamantylglycylglycyl,cyclohexylsarcosylglycyl, cycloheptylsarcosylglycyl,cyclohexylglycylsarcosyl, cyclohexylglycylalanyl, etc.), amino acidresidue having amino acid residue substituted with aryl (e.g.phenylglycylglycyl, phenylsarcosylglycyl, etc.), amino acid residuehaving amino acid residue substituted with acyl {e.g. amino acid residuehaving amino acid residue substituted with alkanoyl (e.g.acetylglycylglycyl, acetylprolylglycyl, propionylglycylglycyl,acetylalanylglycyl, etc.), amino acid residue having amino acid residuesubstituted with lower alkoxycarbonyl (e.g.tert-butoxycarbonylglycylglycyl, tert-butoxycarbonylprolylglycyl, etc.),amino acid residue having amino acid residue substituted with phthaloyl(e.g. phthaloylglycylglycyl, etc.), etc.}, amino acid residue havingamino acid residue substituted with ar(lower)alkyl (e.g.benzylglycylglycyl, etc.), etc.], etc., or the like.

Suitable "acyl having amino" may be unsubstituted amino acid residue,amino acid residue having unsubstituted amino acid residue, or the like,and preferred examples thereof can be referred to those exemplifiedabove.

Suitable "acyl having acylamino" may be amino acid residue substitutedwith acyl, amino acid residue having amino acid residue substituted withacyl, or the like, and preferred examples thereof can be referred tothose exemplified above.

Suitable substituents in the term "amino optionally having suitablesubstituent(s)" may be the above-mentioned lower alkyl, theabove-mentioned acyl, ar(lower)alkyl [e.g. benzyl, phenethyl, trityl,etc.], carboxy(lower)alkyl [e.g. carboxymethyl, carboxyethyl,carboxypropyl, etc.], lower alkoxycarbonyl(lower)alkyl [e.g.methoxycarbonylmethyl, ethoxycarbonylmethyl, methoxycarbonylethyl,ethoxycarbonylpropyl, etc.], heterocyclic(lower)alkyl [e.g.pyridylmethyl, pyridylethyl, etc.], or the like.

Suitable "a leaving group" may be a conventional acid residue such ashalogen [e.g. fluoro, chloro, bromo and iodo], arenesulfonyloxy [e.g.benzenesulfonyloxy, tosyloxy, etc.], alkanesulfonyloxy [e.g. mesyloxy,ethanesulfonyloxy, etc.], and the like.

Suitable pharmaceutically acceptable salts of the object compound [I]are conventional non-toxic salts and include a metal salt such as analkali metal salt [e.g. sodium salt, potassium salt, etc.] and analkaline earth metal salt [e.g. calcium salt, magnesium salt, etc.], anammonium salt, an organic base salt [e.g. trimethylamine salt,triethylamine salt, pyridine salt, picoline salt, dicyclohexylaminesalt, N,N'-dibenzylethylenediamine salt, etc.], an organic acid additionsalt [e.g. formate, acetate, trifluoroacetate, maleate, tartrate,oxalate, methanesulfonate, benzenesulfonate, toluenesulfonate, etc.], aninorganic acid addition salt [e.g. hydrochloride, hydrobromide, sulfate,phosphate, etc.], a salt with an amino acid (e.g. arginine salt,aspartic acid salt, glutamic acid salt, etc.], an intramolecular saltand the like.

Preferred embodiments of the object compound [I] are as follows:

(i) a compound of the formula ##STR9## wherein X is O, S or N--R⁵,

R¹ and R⁵ are each lower alkyl, aryl or ar(lower)alkyl,

R² is hydrogen or halogen,

R³ is halogen,

R⁴ is amino optionally having suitable substituent(s), and

A is lower alkylene; or

(ii) a compound of the formula: ##STR10## wherein X is O, S or N--R⁵,

R¹ and R⁵ are each lower alkyl, lower alkoxy(lower)alkyl, lower alkoxy,lower alkylthio, lower alkylamino, acyl(lower)alkyl, acyl, aryl orar(lower)alkyl,

R² is hydrogen, halogen, lower alkyl or lower alkoxy,

R³ is halogen, lower alkyl or lower alkoxy,

R⁴ is amino optionally having suitable substituent(s), and

A is lower alkylene.

With respect to the salts of the compounds [Ia] to [Ic] in the Processes2 to 3, it is to be noted that these compounds are included within thescope of the compound [I], and accordingly the suitable examples of thesalts of these compounds are to be referred to those as exemplified forthe object compound [I].

The processes for preparing the object compound [I] are explained indetail in the following.

Process 1

The object compound [I] or its salt can be prepared by reacting acompound [II] or its salt with a compound [III] or its salt.

Suitable salts of the compounds [II] and [III] may be the same as thoseexemplified for the compound [I].

The reaction is preferably carried out in the presence of a base such asalkali metal [e.g. lithium, sodium, potassium, etc.], the hydroxide orcarbonate or bicarbonate thereof [e.g. sodium hydroxide, potassiumcarbonate, potassium bicarbonate, etc.], alkali metal alkoxide [e.g.sodium methoxide, sodium ethoxide, potassium tert-butoxide, etc.], orthe like.

This reaction is usually carried out in a conventional solvent such astetrahydrofuran, dioxane, N,N-dimethylformamide, acetone, or the like.

The reaction temperature is not critical, and the reaction is usuallycarried out under cooling to heating.

Process 2

The object compound [Ib] or its salt can be prepared by acylating acompound [Ia] or its salt.

The acylation is carried out in the presence of an acylating agent.

Suitable acylating agents are the corresponding carboxylic acid orsulfonic acid compounds, which are represented by the formula: R--OHwherein R is acyl, and reactive derivatives thereof, and thecorresponding isocyanate or isothiocyanate compounds.

As suitable said reactive derivatives, there may be mentioned acidhalides, acid anhydrides, active amides and active esters. Suitableexamples are acid halides such as acid chloride and acid bromide, mixedacid anhydrides with various acids [e.g. substituted phosphoric acidsuch as dialkyl phosphoric acid, sulfuric acid, aliphatic carboxylicacid, aromatic carboxylic acid, etc.], symmetric acid anhydrides, activeamides with various imidazoles, and active esters such as p-nitrophenylester and N-hydroxysuccinimide ester. The kind of such reactivederivatives can be selected depending on the kind of acyl group to beintroduced.

The reaction is usually carried out in a conventional solvent, such asmethylene chloride, chloroform, pyridine, dioxane, tetrahydrofuran,N,N-dimethylformamide, or the like. In case that the acylating agent isliquid, it can also be used as a solvent. In case that the carboxylicacid or sulfonic acid compounds are used as acylating agent in the freeacid form or salt form, it is preferable to carry out the reaction inthe presence of a conventional condensing agent such asN,N'-dicyclohexylcarbodiimide or the like.

The reaction temperature is not critical and the reaction can be carriedout under cooling, at ambient temperature, or under heating.

This reaction is preferably carried out in the presence of aconventional inorganic base or in the presence of a conventional organicbase.

Process 3

The object compound [Ic] or its salt can be prepared by reacting acompound [IV] or its salt with a compound [V].

Suitable salts of the compound [IV] can be referred to the ones asexemplified for the compound [I].

The reaction is usually carried out in a conventional solvent such asacetic acid, or the like under cooling or at ambient temperature.

The starting compound [IV] or its salt can be prepared, for example, bya process as illustrated in the following reaction scheme. ##STR11##wherein R², R³, R⁴, R⁵, A and Y are each as defined above.

The compound [IV] or its salt can be prepared by reacting a compound[VI] or its salt with a compound [III] or its salt.

Suitable salts of the compound [VI] can be referred to the ones asexemplified for the compound [I].

This reaction can be carried out in substantially the same manner asProcess 1, and therefore the reaction mode and reaction condition ofthis reaction are to be referred to those explained in Process 1.

The object compound [I] and the starting compounds can also be preparedby the methods of Examples and Preparations mentioned below, similarmanners thereto or to those described in EP-A-596,406 and EP-A-622,361,or conventional manners.

The compounds obtained by the above processes can be isolated andpurified by a conventional method such as pulverization,recrystallization, chromatography, reprecipitation or the like.

It is to be noted that the compound [I] and the other compounds mayinclude one or more stereoisomers and geometrical isomers due toasymmetric carbon atoms and double bonds, and all of such isomers andmixture thereof are included within the scop of this invention.

For therapeutic purpose, the compound [I] and a pharmaceuticallyacceptable salt thereof of the present invention can be used in a formof pharmaceutical preparation containing one of said compounds, as anactive ingredient, in admixture with a pharmaceutically acceptablecarrier such as an organic or inorganic solid, semi-solid or liquidexcipient suitable for oral, parenteral such as intravenous,intramuscular, subcutaneous or intraarticular, external such as topical,enteral, intrarectal, transvaginal, inhalant, ophthalmic, nasal ofhypoglossal administration. The pharmaceutical preparations may becapsules, tablets, dragees, granules, suppositories, solution, lotion,suspension, emulsion, ointment, gel, cream, or the like. If desired,there may be included in these preparations, auxiliary substances,stabilizing agents, wetting or emulsifying agents, buffers and othercommonly used additives.

While the dosage of the compound [I] will vary depending upon the ageand condition of the patient, an average single dose of about 0.1 mg, 1mg, 10 mg, 50 mg, 100 mg, 250 mg, 500 mg and 1000 mg of the compound [I]may be effective for preventing and/or treating the above-mentioneddiseases. In general, amounts between 0.1 mg/body and about 1,000mg/body may be administered per day.

In order to illustrate the usefulness of the object compound [I], thepharmacological test data of some representative compounds of thecompound [I] are shown in the following.

³ H-Bradykinin Receptor Binding

(i) Test Method:

(a) Crude ileum membrane preparation

Male Hartly strain guinea pigs were sacrificed by decapitation. Theileum was removed and homogenized in buffer (50 mMtrimethylaminoethanesulfonic acid (TES), 1 mM 1,10-phenanthroline pH6.8). The homogenate was centrifuged (1000×g, 20 minutes) to removetissue clumps and the supernatant was centrifuges (100,000×g, 60minutes) to yield a pellet. The pellet was resuspended in buffer (50 mMTES, 1 mM 1,10-phenanthroline, 140 mg/l bacitracin, 1 mM dithiothreiol,0.1% bovine serum albumin pH 6.8) and homogenized with a glass-teflonhomogenizer to yield suspension which was referred to as crude membranesuspension. The obtained membrane suspension was stored at -80° C. untiluse.

(b) ³ H-Bradykinin Binding to the Membrane

The frozen crude membrane suspension was thawed. In binding assays, ³H-Bradykinin (0.06 nM) and drug (1×10⁻⁵ M) were incubated with 50 μl ofthe membrane suspension at room temperature for 60 minutes in a finalvolume of 250 μl. Separation of receptor-bound from free ³ H-Bradykininis achieved by immediate filtration under vacuum and washed three timeswith 5 ml of ice-cold buffer (50 mM Tris-HCl pH 7.5). Non-specificbinding was defined as binding in the presence of 0.1 μM Bradykinin. Theradioactivity retained on rinsed filters was determined by aliquid-scintillation counter.

(ii) Test Results

    ______________________________________                                                          Inhibition % of                                                               .sup.3 H-Bradykinin                                                           binding (concent-                                           Test Compound (Example No.)                                                                     ration: 1 × 10.sup.-5 M)                              ______________________________________                                        7                 99                                                          15-(9) hydrochloride                                                                            94                                                          15-(20)           98                                                          ______________________________________                                    

The effects of the compound [I] on bradykinin-inducedbronchoconstriction and carrageenin-induced paw edema were measuredaccording to similar manners described in British Journal ofPharmacology, 102, 774-777 (1991).

The object compound [I] and pharmaceutically acceptable salts thereofpossess strong activities as bradykinin antagonists, and are useful forthe treatment and/or the prevention of bradykinin or its analoguesmediated diseases such as allergy, inflammation, autoimmune disease,shock, pain, or the like, and more particularly for the preventionand/or the treatment of asthma, cough, bronchitis, rhinitis, rhinorrhea,obstructive pulmonary disease [e.g. pulmonary emphysema, etc.],expectoration, pneumonitis, systemic inflammatory response syndrome(SIRS), septic shock, endotoxin shock, anaphylactic shock, adultrespiratory distress syndrome, disseminated intravascular coagulopathy,arthritis, rheumatism, osteoarthritis, lumbago, inflammation-inducedbone resorption, conjunctivitis, vernal conjunctivitis, uveitis, iritis,iridocyclitis, headache, migraine, toothache, backache, superficialpain, cancerous pain, postoperative pain, tenalgia, trauma [e.g. wound,burn, etc.], rash, erythema, eczema or dermatitis [e.g. contactdermatitis, atopic dermatitis, etc.], urticaria, herpes, itching,psoriasis, lichen, inflammatory bowel disease [e.g. ulcerative colitis,Crohn's disease, etc.], diarrhea, emesis, hepatitis, pancreatitis,gastritis, esophagitis, food allergy, ulcer, irritable bowel syndrome,nephritis, angina, periodontitis, edema, hereditary angioneurotic edema,cerebral edema, low blood pressure, thrombosis, myocardial infarction,cerebral vasospasm, congestion, coagulation, gout, central nervoussystem injury, premature labor, arteriosclerosis (hyperlipidemia,hypercholesterolemia), postgastrectomy dumping syndrome, carcinoidsyndrome, altered sperm mobility, diabetic neuropathy, neuralgia, graftrejection in transplantation, or the like, in human being or animals.

And further, it is known that bradykinin relates to the release ofmediators such as prostaglandins, leukotrienes, tachykinins, histamine,thromboxanes, or the like, so the compound [I] is expected to be usefulfor the prevention and/or the treatment of such mediators mediateddiseases.

EXAMPLES

The following Preparations and Examples are given for the purpose ofillustrating this invention.

Preparation 1

(1) A suspension of 3-methoxy-2-nitrobenzoic acid (10.0 g),triethylamine (5.13 g) and diphenylphosphoryl azide (14 g) in benzene(100 ml) was refluxed for 40 minutes, and ethanol (2.57 g) was addedthereto, and the mixture was refluxed for 30 minutes. After cooling, thesolvent was removed in vacuo, and the residue was dissolved in ethylacetate. Insoluble material was filtered off, and the filtrate waswashed with saturated sodium bicarbonate solution, water and brine,dried over magnesium sulfate and evaporated in vacuo. The residue waspurified by silica gel column chromatography (hexane:ethyl acetate=4:1,v/v) to give ethyl N-(3-methoxy-2-nitrophenyl)carbamate (7.23 g).

mp: 131-132° C.

NMR (CDCl₃, δ): 1.31 (3H, d, J=7.5 Hz), 3.90 (3H, s), 4.22 (2H, q, J=7.5Hz), 6.73 (1H, d, J=7.5 Hz), 7.41 (1H, t, J=7.5 Hz), 7.71 (1H, br s),7.78 (1H, d, J=7.5 Hz)

(2) To a suspension of lithium aluminum hydride (2.27 g) intetrahydrofuran (50 ml) was added a suspension of ethylN-(3-methoxy-2-nitrophenyl)carbamate (7.17 g) in tetrahydrofuran (15 ml)under ice-cooling, and the mixture was stirred for 1.5 hours at ambienttemperature. Insoluble material was filtered off, and the filtrate waswashed with water and brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by silica gel column chromatography(hexane:ethyl acetate=3:1, v/v) to give2-amino-3-methoxy-N-methylaniline (687 mg).

mp: 60-61° C.

NMR (CDCl₃, δ): 2.88 (3H, s), 3.40 (2H, br s), 3.84 (3H, s), 6.38 (1H,d, J=7.5 Hz), 6.42 (1H, d, J=7.5 Hz), 6.81 (1H, t, J=7.5 Hz)

(3) A suspension of 2-amino-3-methoxy-N-methylaniline (671 mg) andacetic acid (265 mg) in 4N hydrochloric acid (3.5 ml) was refluxed for10 hours. Insoluble material was filtered off, and the filtrate wasadjusted to pH 7 with saturated sodium bicarbonate solution, andextracted with dichloromethane. The organic layers were combined, washedwith brine, dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by silica gel flash chromatography(dichloromethane:methanol=40:1, v/v) to give1,2-dimethyl-4-methoxy-1H-benzimidazole (680 mg).

mp 122.5-124° C.

NMR (CDCl₃, δ): 2.59 (3H, s), 3.70 (3H, s), 4.00 (3H, s), 6.67 (1H, d,J=7.5 Hz), 6.89 (1H, d, J=7.5 Hz), 7.17 (1H, t, J=7.5 Hz)

(4) To a solution of 1,2-dimethyl-4-methoxy-1H-benzimidazole (560 mg) indichloromethane (2 ml) was added 1M boron tribromide-dichloromethanesolution (6.36 ml) under ice-cooling, and the mixture was stirred for 30minutes at the same temperature and then for 2 hours at ambienttemperature, and refluxed for 14 hours. After cooling, the solution wasadjusted to pH 7 with saturated sodium bicarbonate solution, andextracted with dichloromethane twice. The organic layers were combined,washed with brine, dried over magnesium sulfate and evaporated in vacuo.The residue was crystallized with ethyl acetate to give4-hydroxy-1,2-dimethyl-1H-benzimidazole (297 mg).

mp: 242.7-245° C.

NMR (CDCl₃, δ): 2.64 (3H, s), 3.69 (3H, s), 6.81 (2H, d, J=7.5 Hz), 7.17(1H, t, J=7.5 Hz)

Preparation 2

(1) To a suspension of 3-hydroxy-2-nitrobenzoic acid (500 mg) andpotassium carbonate (1.13 g) in dimethylformamide (5 ml) was addedbenzyl bromide (1.12 g) at ambient temperature, and the mixture wasstirred overnight. To the reaction mixture was added water, andextracted with ethyl acetate twice. The organic layers were combined,washed with water and brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by silica gel flash chromatography(hexane-ethyl acetate) and crystallized with diisopropyl ether to givebenzyl 3-benzyloxy-2-nitrobenzoate (676 mg).

mp: 81.7-84.7° C.

NMR (CDCl₃, δ) 5.20 (2H, s), 5.32 (2H, s), 7.22-7.46 (12H, m), 7.61 (1H,d, J=7.5 Hz)

(2) To a suspension of benzyl 3-benzyloxy-2-nitrobenzoate (640 mg) inethanol (5 ml) was added 1N sodium hydroxide solution (1.94 ml) atambient temperature, and the mixture was stirred at 60° C. for 1 hour.The reaction mixture was adjusted to pH 4, and the resultingprecipitates were collected by filtration and dried to give3-benzyloxy-2-nitrobenzoic acid (439 mg).

mp: 198.4-200° C.

NMR (DMSO-d₆, δ): 5.30 (2H, s), 7.29-7.47 (5H, m), 7.51-7.70 (3H, m)

(3) tert-Butyl N-(3-benzyloxy-2-nitrophenyl)carbamate was obtained from3-benzyloxy-2-nitrobenzoic acid, diphenylphosphoryl azide andtert-butanol according to a similar manner to that of Preparation 1-(1).

mp: 139.6-141° C.

NMR (CDCl₃, δ): 1.51 (9H, s), 5.18 (2H, s), 6.76 (1H, d, J=7.5 Hz),7.29-7.45 (6H, m), 7.59 (1H, br s), 7.79 (1H, d, J=7.5 Hz)

Preparation 3

To a solution of tert-butyl N-(3-benzyloxy-2-nitrophenyl) carbamate (3g) in dimethylformamide (30 ml) was added sodium hydride (60% in oil,575 mg) under ice-cooling, and the mixture was stirred for 15 minutes.To the mixture was added ethyl iodide (1.49 g), and the mixture wasstirred for 2 hours at ambient temperature. To the reaction mixture wasadded water (150 ml), and extracted with ethyl acetate. The organiclayer was washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by silica gel columnchromatography (hexane:ethyl acetate=5:1, v/v) and crystallized withhexane to give tert-butyl N-(3-benzyloxy-2-nitrophenyl)-N-ethylcarbamate(3.36 g).

mp: 86.7-92.9° C.

NMR (CDCl₃, δ): 1.17 (3H, t, J=7 Hz), 1.39 (9H, br s), 3.41-3.80 (2H,m), 15.19 (2H, s), 8.86 (1H, br d, J=7.5 Hz), 7.01 (1H, d, J=7.5 Hz),7.29-7.32 (6H, m)

Preparation 4

The following compounds were obtained according to a similar manner tothat of Preparation 3.

(1) tert-Butyl N-(3-benzyloxy-2-nitrophenyl) -N-methylcarbamate wasobtained from tert-butyl N-(3-benzyloxy-2-nitrophenyl) carbamate andmethyl iodide.

mp: 113-115° C.

NMR (CDCl₃, δ): 1.38 (9H, br s), 3.19 (3H, s), 5.19 (2H, s), 6.87 (1H,br d, J=8.5 Hz), 7.00 (1H, d, J=8.5 Hz), 7.31-7.43 (6H, m)

(2) tert-Butyl N-benzyl-N-(3-benzyloxy-2-nitrophenyl)carbamate wasobtained from tert-butyl N-(3-benzyloxy-2-nitrophenyl)carbamate andbenzyl bromide.

mp: 122.4° C.

NMR (CDCl₃, δ): 1.42 (9H, br s), 5.18 (2H, s), 6.97 (1H, d, J=7 Hz),7.18 (1H, br t, J=7 Hz), 7.24-7.43 (11H, m)

Preparation 5

To tert-butyl N-(3-benzyloxy-2-nitrophenyl)-N-ethylcarbamate (3.30 g)was added 4N hydrogen chloride-ethyl acetate solution (15 ml) underice-cooling, and the mixture was stirred for 10 minutes at the sametemperature and then for 30 minutes at ambient temperature. The solventwas removed in vacuo, saturated sodium bicarbonate solution was added tothe residue, and the mixture was extracted with ethyl acetate. Theorganic layer was washed with water and brine, dried over magnesiumsulfate and evaporated in vacuo to give3-benzyloxy-N-ethyl-2-nitroaniline (2.29 g).

NMR (CDCl₃, δ): 1.30 (3H, t, J=7 Hz), 3.13 (2H, q, J=7 Hz), 5.16 (2H,s), 6.31 (1H, d, J=7.5 Hz), 6.38 (1H, d, J=7.5 Hz), 7.21 (1H, t, J=7.5Hz), 7.28-7.49 (5H, m)

Preparation 6

The following compounds were obtained according to a similar manner tothat of Preparation 5.

(1) 3-Benzyloxy-N-methyl-2-nitroaniline

mp: 80-81° C.

NMR (CDCl₃, δ): 2.91 (3H, d, J=7.0 Hz), 5.15 (2H, s), 6.21 (1H, br d,J=7.0 Hz), 6.33 (1H, d, J=8.5 Hz), 6.38 (1H, d, J=8.5 Hz), 7.25 (1H, t,J=8.5 Hz), 7.29-7.49 (5H, m)

(2) N-Benzyl-3-benzyloxy-2-nitroaniline

mp: 91.5-93.7° C.

NMR (CDCl₃, δ): 4.42 (2H, d, J=6 Hz), 5.66 (2H, s), 6.33 (1H, d, J=7Hz), 6.34 (1H, d, J=7 Hz), 6.47 (1H, br t, J=6 Hz), 7.15 (1H, t, J=7.5Hz), 7.24-7.49 (10H, m)

Preparation 7

To a solution of 3-benzyloxy-N-ethyl-2-nitroaniline (2.20 g) andtriethylamine (1.23 g) in dichloromethane (21 ml) was added acetylchloride (698 mg) under ice-cooling, and the mixture was stirred for 3hours at ambient temperature. The reaction mixture was washed withwater, saturated sodium bicarbonate solution, water and brinesuccessively, dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by silica gel flash chromatography(dichloromethane-ethyl acetate) to giveN-acetyl-3-benzyloxy-N-ethyl-2-nitroaniline (1.71 g).

NMR (CDCl₃, δ): 1.15 (3H, t, J=7 Hz), 2.18 (3H, s), 3.16-4.10 (2H, m),5.13 (2H, s), 6.90 (1H, d, J=7.5 Hz), 7.18 (1H, d, J=7.5 Hz), 7.33-7.50(6H, m)

Preparation 8

The following compounds were obtained according to a similar manner tothat of Preparation 7.

(1) 3-Benzyloxy-N-benzoyl-N-methyl-2-nitroaniline was obtained from3-benzyloxy-N-methyl-2-nitroaniline and benzoyl chloride.

NMR (CDCl₃, δ): 3.37 (3H, s), 5.17 (2H, s), 6.60 (1H, br d, J=8.5 Hz),6.93 (1H, d, J=8.5 Hz), 7.12-7.50 (11H, m)

(2) 3-Benzyloxy-N-methyl-2-nitro-N-propionylaniline was obtained from3-benzyloxy-N-methyl-2-nitroaniline and propionyl chloride.

NMR (CDCl₃, δ) 0.91 (1H, t, J=7.5 Hz), 1.16 (2H, t, J=7.5 Hz), 1.95-2.22(1.3H, m), 2.33-2.60 (0.7H, m), 3.15-3.27 (3H, m), 5.16-5.25 (2H, m),6.83-6.94 (1H, m), 7.09-7.20 (1H, m), 7.30-7.53 (6H, m)

(3) N-Acetyl-N-benzyl-3-benzyloxy-2-nitroaniline was obtained fromN-benzyl-3-benzyloxy-2-nitroaniline and acetyl chloride.

NMR (CDCl₃, δ): 1.92 (2H, s), 2.16 (1H, s), 3.22 (0.5H, d, J=15 Hz),3.44 (0.5H, d, J=15 Hz), 3.98 (1H, d, J=15 Hz), 4.03 (1H, d, J=15 Hz),5.19 (2H, s), 5.57 (0.5H, br s), 5.62 (0.5H, br s), 6.33 (0.6H, d, J=7.5Hz), 6.38 (0.4H, d, J=7.5 Hz), 7.04-7.13 (1H, m), 7.17-7.45 (10H, m)

Preparation 9

To a solution of N-acetyl-3-benzyloxy-N-ethyl-2-nitroaniline (1.37 g) inacetic acid (11 ml) and ethanol (2.7 ml) was added iron (2.43 g), andthe mixture was refluxed for 4 hours. Insoluble material was filteredoff, and the filtrate was concentrated in vacuo. To the residue wasadded saturated sodium bicarbonate solution, and extracted with ethylacetate. The organic layer was washed with saturated sodium bicarbonatesolution, water and brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by silica gel flash chromatography(hexane-ethyl acetate) to give4-benzyloxy-1-ethyl-2-methyl-1H-benzimidazole (397 mg).

NMR (CDCl₃, δ): 1.40 (3H, t, J=7.5 Hz), 2.61 (3H, s), 4.13 (2H, q, J=7.5Hz), 5.37 (2H, s), 6.67 (1H, d, J=7.5 Hz), 6.91 (1H, d, J=7.5 Hz), 7.09(1H, t, J=7.5 Hz), 7.26-7.40 (3H, m), 7.51 (2H, br d, J=7.5 Hz)

Preparation 10

The following compounds were obtained according to a similar manner tothat of Preparation 9.

(1) 4-Benzyloxy-1-methyl-2-phenyl-1H-benzimidazole

mp: 118-120° C.

NMR (CDCl₃, δ): 3.85 (3H, s), 5.47 (2H, s), 6.73 (1H, d, J=7.5 Hz), 6.99(1H, d, J=7.5 Hz), 7.17 (1H, t, J=7.5 Hz), 7.25-7.39 (3H, m), 7.48-7.57(5H, m), 7.77-7.84 (2H, m)

(2) 4-Benzyloxy-2-ethyl-1-methyl-1H-benzimidazole

mp: 94.9° C.

NMR (CDCl₃, δ) 1.43 (3H, t, J=7.5 Hz), 2.95 (2H, q, J=7.5 Hz), 3.70 (3H,s), 5.39 (2H, s), 6.65 (1H, d, J=8 Hz), 6.89 (1H, d, J=8 Hz), 7.09 (1H,t, J=8 Hz), 7.25-7.40 (3H, m), 7.51 (2H, d-like)

(3) 1-Benzyl-4-benzyloxy-2-methyl-1H-benzimidazole

mp 128.5-136.8° C.

NMR (CDCl₃, δ): 2.56 (3H, s), 5.29 (2H, s), 5.37 (2H, s), 6.68 (1H, d,J=7.5 Hz), 6.83 (1H, d, J=7.5 Hz), 6.99-7.10 (3H, m), 7.24-7.44 (6H, m),7.53 (2H, br d, J=9 Hz)

Preparation 11

To a solution of 4-benzyloxy-1-ethyl-2-methyl-1H-benzimidazole (370 mg)in ethyl acetate (3.7 ml) was added 10% palladium on carbon (18 mg), andthe mixture was stirred for 5 hours at ambient temperature underhydrogen atmosphere. Insoluble material was filtered off, and thefiltrate was concentrated in vacuo. The residue was crystallized withdiisopropyl ether to give 1-ethyl-4-hydroxy-2-methyl-1H-benzimidazole(220 mg)

mp: 187-190° C.

NMR (CDCl₃, δ): 1.40 (3H, t, J=7.5 Hz), 2.68 (3H, s), 4.13 (2H, q, J=7.5Hz), 6.81 (1H, d, J=7.5 Hz), 6.84 (1H, d, J=7.5 Hz), 7.17 (1H, t, J=7.5Hz)

Preparation 12

The following compounds were obtained according to a similar manner tothat of Preparation 11.

(1) 1-Methyl-4-hydroxy-2-phenyl-1H-benzimidazole

mp: 210-211° C.

NMR (DMSO-d₆, δ): 3.82 (3H, s), 6.59 (1H, d, J=8.5 Hz), 7.00 (1H, d,J=8.5 Hz), 7.07 (1H, t, J=8.5 Hz), 7.50-7.62 (3H, m), 7.79-7.87 (2H, m)

(2) 2-Ethyl-4-hydroxy-1-methyl-1H-benzimidazole

mp: 233.2° C.

NMR (CDCl₃, δ): 1.36 (3H, t, J=7.5 Hz), 2.98 (2H, q, J=7.5 Hz), 3.70(3H, s), 6.77-6.86 (2H, m), 7.15 (1H, t, J=8 Hz)

(3) 1-Benzyl-4-hydroxy-2-methyl-1H-benzimidazole

mp: 212.1° C.

NMR (CDCl₃, δ): 2.61 (3H, s), 5.28 (2H, s), 6.75 (1H, d, J=8 Hz), 6.80(1H, d, J=8 Hz), 7.00-7.16 (2H, m), 7.11 (1H, t, J=8 Hz), 7.19-7.34 (3H,m)

Preparation 13

(1) To a solution of 2,6-dichloro-3-nitrobenzyl alcohol (5.0 g) inN,N-dimethylformamide (25 ml) were added imidazole (1.69 g) andtert-butyldiphenylsilyl chloride (6.0 ml) at ambient temperature withstirring. After 8 hours, the mixture was diluted with water (25 ml) andwas extracted with ethyl acetate twice. The organic layer was washedwith water and brine, dried over magnesium sulfate. The solvent wasremoved in vacuo to give1-(tert-butyldiphenylsilyloxy-methyl)-2,6-dichloro-3-nitrobenzene (11.5g) as an oil.

NMR (CDCl₃, δ): 1.05 (9H, s), 4.96 (2H, s), 7.27-7.51 (7H, m), 7.58-7.81(5H, m)

(2) To a stirred mixture of1-(tert-butyldiphenylsilyloxy-methyl)-2,6-dichloro-3-nitrobenzene (433mg), ferric chloride hexahydrate (17.5 mg) and activated carbon (17.5mg) in a mixture of methanol (2.78 ml) and water (0.69 ml) was addedhydrazine monohydrate (0.135 ml) dropwise at 60-70° C. After theaddition was finished, the mixture was refluxed for half an hour. Themixture was allowed to cool and filtered. The filtrate was concentratedin vacuo. The residue was extracted with dichloromethane and the organicphase was dried over anhydrous magnesium sulfate. After being filtered,the filtlate was concentrated in vacuo and the resulting residue waswashed with n-hexane to give3-amino-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichlorobenzene (348mg) as a white mass.

NMR (CDCl₃, δ): 1.05 (9H, s), 4.07 (2H, br s), 4.87 (2H, s), 6.66 (1H,d, J=9 Hz), 7.08 (1H, d, J=9 Hz), 7.30-7.50 (6H, m), 7.70-7.84 (4H, m)

(3) To a mixture of3-amino-1-(tert-butyldiphenylsilyloxy-methyl)-2,6-dichlorobenzene (348mg) triethylamine (0.15 ml) and dichloromethane (3.5 ml) was addedphthalimidoacetyl chloride (186 mg) under ice-cooling, and the mixturewas stirred for 1.5 hours at ambient temperature. Water was addedthereto, and the resulting precipitates were collected by vacuumfiltration and washed with diisopropyl ether to give1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-(phthalimidoacetylamino)benzene(460 mg) as crystals.

mp: 198.1° C.

NMR (CDCl₃, δ): 1.04 (9H, s), 4.57 (2H, s), 4.90 (2H, s), 7.25-7.50 (7H,m), 7.55-7.83 (6H, m), 7.85-8.07 (2H, m), 8.00 (1H, br s), 8.25 (1H, d,J=8 Hz)

(4) To a mixture of1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-(phthalimidoacetylamino)benzene(453 mg) and N,N-dimethylformamide (2.2 ml) was added sodium hydride(60% in oil, 31 mg) under ice-cooling, and the mixture was stirred for50 minutes. To the mixture was added methyl iodide (0.055 ml), and themixture was stirred for 2.5 hours at ambient temperature. Water (88 ml)was added to the mixture under ice-cooling, and the resultingprecipitates were collected by vacuum filtration and washed with waterand ethyl acetate to give1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene(236 mg) as powder.

mp: 167-172° C.

NMR (CDCl₃, δ): 1.06 (9H, s), 3.20 (3H, s), 4.04 (2H, s), 4.98 (2H, s),7.31-7.51 (9H, m), 7.65-7.79 (6H, m), 7.80-7.92 (2H, m)

(5) To a solution of1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene(119 mg) in tetrahydrofuran (0.6 ml) was added 1M tetrabutylammoniumfluoride-tetrahydrofuran (0.4 ml) under ice-cooling, and the mixture wasstirred for 1.5 hours at ambient temperature. The mixture waspartitioned between ethyl acetate and water. The organic layer wasconcentrated in vacuo.

The resulting precipitates were collected by filtration and washed withmethanol to give2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene(43 mg) as powder.

mp 236.2-240.8° C.

NMR (CDCl₃, δ): 2.24 (1H, t, J=7 Hz), 3.21 (3H, s), 4.09 (2H, s), 5.04(2H, d, J=7 Hz), 7.43 (1H, d, J=8 Hz), 7.48 (1H, d, J=8 Hz), 7.67-7.75(2H, m), 7.80-7.88 (2H, m)

(6) To a mixture of2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene (399 mg) and triethylamine (0.17 ml) in methylene chloride(8 ml) was added methanesulfonyl chloride (0.086 ml) under -20° C., andthe mixture was stirred for 1 hour. The mixture was washed with sodiumbicarbonate solution and brine, dried over magnesium sulfate andconcentrated in vacuo to give2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene(561 mg).

NMR (CDCl₃, δ): 3.15 (3H, s), 3.24 (3H, s), 4.09 (2H, s), 5.48 (2H, s),7.56 (2H, s), 7.67-7.78 (2H, m), 7.80-7.93 (2H, m)

Example 1

To a suspension of 4-hydroxy-1,2-dimethyl-1H-benzimidazole (250 mg) inN,N-dimethylformamide (2.5 ml) was added sodium hydride (60% in oil, 102mg) under ice-cooling, and the mixture was stirred for 15 minutes atambient temperature. To the mixture was added2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)-amino]benzene(799 mg), and the mixture was stirred for 3 hours at ambienttemperature. Water was dropwise added thereto, and the resultingprecipitates were collected by filtration to give4-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-1,2-dimethyl-1H-benzimidazole(418 mg).

mp: 225.6-227° C.

NMR (CDCl₃, δ): 2.59 (3H, s), 3.23 (3H, s), 3.71 (3H, s), 4.11 (2H, s),5.60 (2H, s), 6.85 (1H, d, J=7.5 Hz), 6.98 (1H, d, J=7.5 Hz), 7.21 (1H,t, J=7.5 Hz), 7.48 (1H, d, J=8 Hz), 7.52 (1H, d, J=8 Hz), 7.69-7.77(2H), 7.82-7.90 (2H)

Example 2

The following compounds were obtained according to a similar manner tothat of Example 1.

(1)4-[2,6-Dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]-benzyloxy]-2-methylbenzoxazolewas obtained from 4-hydroxy-2-methylbenzoxazole and2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene.

mp 204.7-206.5° C.

NMR (CDCl₃, δ): 2.62 (3H, s), 3.24 (3H, s), 4.12 (2H, s), 5.63 (2H, s),6.94 (1H, d, J=7.5 Hz), 7.18 (1H, d, J=7.5 Hz), 7.23-7.31 (1H,overlapped with CDCl₃), 7.50 (1H, d, J=8 Hz), 7.54 (1H, t, J=8 Hz),7.69-7.77 (2H), 7.82-7.89 (2H)

(2)4-[2,6-Dichloro-3-[N-(phthalimidoacetyl)-N-methyl-amino]benzyloxy]-1-ethyl-2-methyl-1H-benzimidazole

mp: 233-236° C.

NMR (CDCl₃, δ): 1.40 (3H, t, J=7.5 Hz), 2.59 (3H, s), 3.24 (3H, s),4.09-4.20 (4H, m), 5.60 (2H, s), 6.85 (1H, d, J=7.5 Hz), 6.99 (1H, d,J=7.5 Hz), 7.21 (1H, t, J=7.5 Hz), 7.48 (1H, d, J=8 Hz), 7.51 (1H, d,J=8 Hz), 7.69-7.77 (2H, m), 7.83-7.89 (2H, m)

(3)4-[2,6-Dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]-benzyloxy]-1-methyl-2-phenyl-1H-benzimidazole

mp: 154-156° C.

NMR (CDCl₃, δ): 3.21 (3H, s), 3.83 (3H, s), 4.09 (2H, s), 5.71 (2H, s),6.91 (1H, d, J=7.5 Hz), 7.08 (1H, d, J=7.5 Hz), 7.27 (1H, t, J=7.5 Hz),7.43-7.53 (5H, m), 7.66-7.77 (4H, m), 7.80-7.89 (2H, m)

(4)4-[2,6-Dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]-benzyloxy]-2-ethyl-1-methyl-1H-benzimidazole

mp: 108.1° C.

NMR (CDCl₃, δ): 1.37 (3H, t, J=7.5 Hz), 2.93 (2H, q, J=7.5 Hz), 3.24(3H, s), 3.73 (3H, s), 4.10 (2H, s), 5.63 (2H, s), 6.85 (1H, d, J=8 Hz),6.97 (1H, d, J=8 Hz), 7.19 (1H, t, J=8 Hz), 7.46 (1H, d, J=8 Hz), 7.52(1H, d, J=8 Hz), 7.67-7.75 (2H, m), 7.80-7.90 (2H, m)

(5)4-[2,6-Dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]-benzyloxy]-1-benzyl-2-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 2.54 (3H, s), 3.24 (3H, s), 4.14 (2H, s), 5.30 (2H, s),5.60 (2H, s), 6.85 (1H, d, J=7.5 Hz), 6.93 (1H, d, J=7.5 Hz), 7.03-7.10(2H, m), 7.17 (1H, t, J=7.5 Hz), 7.24-7.36 (3H, m), 7.47 (1H, d, J=8Hz), 7.51 (1H, d, J=8 Hz), 7.68-7.75 (2H, m), 7.80-7.90 (2H, m)

Example 3

A mixture of4-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-1,2-dimethyl-1H-benzimidazole(405 mg), hydrazine monohydrate (75.4 mg) and ethanol (4.0 ml) wasrefluxed for 30 minutes. After cooling, the resulting precipitate wasfiltered off, and the filtrate was concentrated in vacuo to give4-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole(300 mg).

NMR (CDCl₃, δ): 2.59 (3H, s), 3.02 (1H, d, J=17 Hz), 3.12 (1H, d, J=17Hz), 3.22 (3H, s), 3.71 (3H, s), 5.52 (1H, d, J=10 Hz), 5.58 (1H, d,J=10 Hz), 6.82 (1H, d, J=7.5 Hz), 6.97 (1H, d, J=7.5 Hz), 7.20 (1H, t,J=7.5 Hz), 7.23 (1H, d, J=8 Hz), 7.43 (1H, d, J=8 Hz)

Example 4

The following compounds were obtained according to a similar manner tothat of Example 3.

(1)4-[3-(N-Glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylbenzoxazole

NMR (CDCl₃, δ): 2.61 (3H, s), 3.02 (1H, d, J=17 Hz), 3.12 (1H, d, J=17Hz), 3.22 (3H, s), 5.57 (1H, d, J=10 Hz), 5.61 (1H, d, J=10 Hz), 6.92(1H, d, J=7.5 Hz), 7.17 (1H, d, J=7.5 Hz), 7.22-7.30 (2H), 7.46 (1H, d,J=7.5 Hz)

(2)4-[3-(N-Glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-1-ethyl-2-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 1.40 (3H, t, J=7.5 Hz), 2.59 (3H, s), 3.02 (1H, d, J=17Hz), 3.12 (1H, d, J=17 Hz), 3.22 (3H, s), 4.14 (2H, d, J=7.5 Hz), 5.52(1H, d, J=10 Hz), 5.58 (1H, d, J=10 Hz), 6.83 (1H, d, J=7.5 Hz), 6.98(1H, d, J=7.5 Hz), 7.17-7.28 (2H, m), 7.43 (1H, d, J=8 Hz)

(3)4-[3-(N-Glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-1-methyl-2-phenyl-1H-benzimidazole

NMR (CDCl₃, δ): 3.02 (1H, d, J=16.5 Hz), 3.12 (1H, d, J=16.5 Hz), 3.22(3H, s), 3.84 (3H, s), 5.65 (1H, d, J=9.0 Hz), 5.70 (1H, d, J=9.0 Hz),6.89 (1H, d, J=7.5 Hz), 7.07 (1H, d, J=7.5 Hz), 7.23 (1H, d, J=7.5 Hz),7.29 (1H, t, J=7.5 Hz), 7.43 (1H, d, J=7.5 Hz), 7.47-7.53 (3H, m),7.70-7.78 (2H, m)

(4)4-[3-(N-Glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-ethyl-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ) 1.36 (3H, t, J=7.5 Hz), 2.93 (2H, q, J=7.5 Hz), 3.03 (1H,d, J=18 Hz), 3.11 (1H, d, J=18 Hz), 3.23 (3H, s), 3.73 (3H, s),5.53-5.65 (2H, m), 6.84 (1H, d, J=8 Hz), 6.97 (1H, d, J=8 Hz), 7.15-7.28(2H, m), 7.45 (1H, d, J=8 Hz)

(5)4-[3-(N-Glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-1-benzyl-2-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 1.77 (2H, br s), 2.55 (3H, s), 3.03 (1H, d, J=17 Hz),3.10 (1H, d, J=17 Hz), 3.21 (3H, s), 5.30 (2H, s), 5.54 (1H, d, J=9 Hz),5.59 (1H, d, J=9 Hz), 6.83 (1H, d, J=7 Hz), 6.90 (1H, d, J=7 Hz),7.00-7.10 (2H, m), 7.16 (1H, t, J=7 Hz), 7.20-7.35 (4H, m), 7.43 (1H, d,J=7 Hz)

Example 5

To a solution of 4-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole (80 mg) indichloromethane (0.8 ml) were added pyridine (23.3 mg) and aceticanhydride (30.1 mg) at ambient temperature, and the mixture was stirredfor 1 hour at the same temperature. The solvent was removed with tolueneazeotropically three times. The residue was purified by preparative thinlayer chromatography (dichloromethane:methanol=10:1, v/v) to give4-[3-[N-(acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole(75 mg).

NMR (CDCl₃, δ): 2.01 (3H, s), 2.58 (3H, s), 3.24 (3H, s), 3.52 (1H, dd,J=17, 4 Hz), 3.71 (3H, s), 3.80 (1H, dd, J=17, 5 Hz), 5.51 (1H, d, J=10Hz), 5.58 (1H, d, J=10 Hz), 6.42 (1H, br s), 6.86 (1H, d, J=7.5 Hz),6.98 (1H, d, J=7.5 Hz), 7.18-7.29 (2H), 7.47 (1H, d, J=7.5 Hz)

Example 6

4-[3-[N-(Acetylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylbenzoxazolewas obtained according to a similar manner to that of Example 5.

NMR (CDCl₃, δ): 2.01 (3H, s), 2.61 (3H, s), 3.24 (3H, s), 3.51 (1H, dd,J=17, 4 Hz), 3.80 (1H, dd, J=17, 4 Hz), 5.55 (1H, d, J=10 Hz), 5.60 (1H,d, J=10 Hz), 6.42 (1H, br s), 6.92 (1H, d, J=7.5 Hz), 7.16 (1H, d, J=7.5Hz), 7.22-7.31 (2H), 7.48 (1H, d, J=7.5 Hz)

Example 7

To a mixture of4-[3-(N-glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole(100 mg), 4-(methylcarbamoyl)cinnamic acid (55.4 mg) anddimethylformamide (1 ml) were added1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (61.2 mg)and 1-hydroxybenzotriazole (49.7 mg), and the mixture was stirred for 3hours at ambient temperature. To the mixture was added water, and themixture was extracted with dichloromethane. The separated organic layerwas washed with saturated sodium bicarbonate solution and brine, driedover magnesium sulfate and evaporated in vacuo. The residue was purifiedby preparative thin layer chromatography (dichloromethane-methanol) togive4-[2,6-dichloro-3-[N-methyl-N-[4-(methyl-carbamoyl)cinnamoylglycyl]amino]benzyloxy]]-1,2-dimethyl-1H-benzimidazole(121 mg).

NMR (CDCl₃, δ): 2.58 (3H, s), 3.02 (3H, d, J=5 Hz), 3.28 (3H, s),3.61-3.72 (4H), 3.93 (1H, dd, J=17, 5 Hz), 5.52 (1H, d, J=10 Hz), 5.58(1H, d, J=10 Hz), 6.20 (1H, br d, J=5 Hz), 6.52 (1H, d, J=15 Hz), 6.70(1H, br s), 6.88 (1H, d, J=7.5 Hz), 6.98 (1H, d, J=7.5 Hz), 7.22 (1H, t,J=7.5 Hz), 7.30 (1H, d, J=8 Hz), 7.48 (1H, d, J=8 Hz), 7.51-7.62 (3H),7.77 (2H, d, J=7.5 Hz)

Example 8

The following compounds were obtained according to a similar manner tothat of Example 7.

(1)4-[2,6-Dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)-cinnamoylglycyl]amino]benzyloxy]-2-methylbenzoxazole

NMR (CDCl₃, δ): 2.61 (3H, s), 3.02 (3H, d, J=5 Hz), 3.28 (3H, s), 3.67(1H, dd, J=17, 4 Hz), 3.94 (1H, dd, J=17, 5 Hz), 5.58 (1H, d, J=10 Hz),5.61 (1H, d, J=10 Hz), 6.15 (1H, br d, J=5 Hz), 6.52 (1H, d, J=15 Hz),6.68 (1H, br s), 6.93 (1H, d, J=7.5 Hz), 7.16 (1H, d, J=7.5 Hz),7.21-7.35 (3H), 7.46-7.62 (3H), 7.76 (2H, d, J=7.5 Hz)

(2)4-[2,6-Dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)-cinnamoylglycyl]amino]benzyloxy]-1-ethyl-2-methyl-1H-benzimidazole

NMR (CDCl₃, δ) 1.40 (3H, t, J=7 Hz), 2.58 (3H, s), 3.02 (3H, d, J=5 Hz),3.28 (3H, s), 3.68 (1H, dd, J=17, 4 Hz), 3.94 (1H, dd, J=17, 5 Hz), 5.52(1H, d, J=10 Hz), 5.58 (1H, d, J=10 Hz), 6.20 (1H, br d, J=5 Hz), 6.52(1H, d, J=15 Hz), 6.70 (1H, br t, J=5 Hz), 6.86 (1H, d, J=7.5 Hz), 6.99(1H, d, J=7.5 Hz), 7.22 (1H, t, J=7.5 Hz), 7.31 (1H, d, J=8 Hz), 7.48(1H, d, J=8 Hz), 7.51-7.62 (3H), 7.76 (2H, d, J=7.5 Hz)

(3)4-[2,6-Dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)-cinnamoylglycyl]amino]benzyloxy]-1-methyl-2-phenyl-1H-benzimidazole

NMR (CDCl₃, δ): 2.98 (3H, d, J=4.5 Hz), 3.25 (3H, s), 3.66 (1H, dd,J=16.5, 4.5 Hz), 3.82 (3H, s), 3.93 (1H, dd, J=16.5, 4.5 Hz), 5.66 (2H,s), 6.24 (1H, br q, J=4.5 Hz), 6.51 (1H, d, J=16.0 Hz), 6.71 (1H, br t,J=4.5 Hz), 6.93 (1H, d, J=7.5 Hz), 7.08 (1H, d, J=7.5 Hz), 7.25-7.34(2H, m), 7.43-7.61 (7H, m), 7.68-7.79 (4H, m)

its hydrochloride

mp: 178-191° C.

NMR (DMSO-d₆, δ): 2.80 (3H, d, J=4.5 Hz), 3.16 (3H, s), 3.53 (1H, dd,J=16.0, 5.5 Hz), 3.82 (1H, dd, J=16.0, 5.5 Hz), 3.97 (3H, s), 5.58 (1H,d, J=10.0 Hz), 5.62 (1H, d, J=10.0 Hz), 6.89 (1H, d, J=16.0 Hz), 7.41(1H, d, J=16.0 Hz), 7.37-7.49 (1H, m), 7.60-7.73 (7H, m), 7.81-7.94 (6H,m), 8.37 (1H, t, J=5.5 Hz), 8.52 (1H, q, J=4.5 Hz)

(4)4-[2,6-Dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)-cinnamoylglycyl]amino]benzyloxy]-2-ethyl-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 1.36 (3H, t, J=7.5 Hz), 2.93 (2H, q, J=7.5 Hz), 3.02(3H, d, J=4.5 Hz), 3.27 (3H, s), 3.66 (1H, dd, J=4, 18 Hz), 3.73 (3H,s), 3.93 (1H, dd, J=4, 18 Hz), 5.53-5.64 (2H, m), 6.17 (1H, q-like),6.52 (1H, d, J=16 Hz), 6.68 (1H, t-like), 6.86 (1H, d, J=8 Hz), 6.98(1H, d, J=8 Hz), 7.21 (1H, t, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.46 (1H,d, J=8 Hz), 7.54 (2H, d, J=8 Hz), 7.59 (1H, d, J=16 Hz), 7.75 (2H, d,J=8 Hz)

its hydrochloride

NMR (DMSO-d₆, δ): 1.27-1.37 (3H, m), 2.78 (3H, d, J=4.5 Hz), 3.12 (2H,q, J=7.5 Hz), 3.15 (3H, s), 3.84 (1H, dd, J=4.5, 16 Hz), 3.95 (3H, s),5.53 (1H, d, J=10 Hz), 5.60 (1H, d, J=10 Hz), 6.86-6.97 (1H, m),7.37-7.49 (2H, m), 7.49-7.78 (4H, m), 7.78-7.91 (4H, m), 8.38 (1H,t-like), 8.52 (1H, q-like)

(5)4-[2,6-Dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)-cinnamoylglycyl]amino]benzyloxy]-1-benzyl-2-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 2.54 (3H, s), 3.00 (3H, d, J=5 Hz), 3.27 (3H, s), 3.66(1H, dd, J=17, 4 Hz), 3.94 (1H, dd, J=17, 5 Hz), 5.30 (2H, s), 5.53 (1H,d, J=9 Hz), 5.58 (1H, d, J=9 Hz), 6.26 (1H, br q, J=5 Hz), 6.50 (1H, d,J=15 Hz), 6.70 (1H, t, J=5 Hz), 6.86 (1H, d, J=7 Hz), 6.91 (1H, d, J=7Hz), 7.02-7.10 (2H, m), 7.17 (1H, t, J=7 Hz), 7.24-7.36 (4H, m),7.44-7.61 (4H, m), 7.70-7.79 (2H, m)

its hydrochloride

NMR (CDCl₃ --CD₃ OD, δ) 2.89 (3H, s), 2.95 (3H, s), 3.27 (3H, s), 3.77(1H, d, J=17 Hz), 3.88 (1H, d, J=17 Hz), 5.51 (1H, d, J=9 Hz), 5.58 (2H,br s), 5.60 (1H, d, J=9 Hz), 6.65 (1H, d, J=15 Hz), 7.10-7.25 (4H, m),7.32-7.41 (2H, m), 7.45-7.60 (7H, m), 7.76 (2H, d, J=9 Hz)

Preparation 14

(1) To a solution of 2-amino-3-nitrophenol (10 g) in dimethylformamide(100 ml) was added potassium carbonate (17.9 g) under ice-cooling, andthe mixture was stirred for 30 minutes at the same temperature. To themixture was added 4-methoxybenzyl chloride (10.7 g) at ambienttemperature, and the mixture was stirred for 30 minutes underice-cooling and then overnight at ambient temperature. To the reactionmixture was added water, and the mixture was extracted withdichloromethane, and purified by silica gel column chromatography (ethylacetate-n-hexane). The residue was crystallized with ethanol to give2-(4-methoxybenzyloxy)-6-nitroaniline (13.6 mg) as yellow needles.

mp: 103° C.

NMR (CDCl₃, δ): 3.84 (3H, s), 5.04 (2H, s), 6.43 (2H, br s), 6.59 (1H,t, J=8 Hz), 6.87-7.01 (3H, m), 7.28-7.40 (2H, br d, J=9 Hz), 7.74 (1H,d, J=8 Hz)

(2) To a solution of 2-(4-methoxybenzyloxy)-6-nitroaniline (3 g) inacetic acid (6 ml) and ethanol (24 ml) was added iron (3.06 g), and themixture was refluxed for 3 hours. Insoluble material was filtered off,and the filtrate was concentrated in vacuo. To the residue was addedsaturated sodium bicarbonate solution, and extracted with ethyl acetate.The organic layer was dried over magnesium sulfate and evaporated invacuo. The residue was pulverized with diethyl ether to give2-amino-3-(4-methoxybenzyloxy)aniline (2.25 g).

mp: 127.1° C.

NMR (CDCl₃, δ): 3.43 (4H, br s), 3.81 (3H, s), 4.98 (2H, s), 6.40 (1H,d, J=8 Hz), 6.48 (1H, d, J=8 Hz), 6.66 (1H, t, J=8 Hz), 6.91 (2H, d, J=9Hz), 7.35 (2H, d, J=9 Hz)

(3) To a stirred solution of 2-amino-3-(4-methoxybenzyloxy)-aniline(1.15 g) in acetic acid (12 ml) was added triethyl orthopropionate (994mg) at ambient temperature, and the mixture was stirred overnight. Thereaction mixture was concentrated in vacuo, and the residue wasextracted with dichloromethane. The organic layer was washed withsaturated sodium bicarbonate solution and brine, dried over magnesiumsulfate and evaporated in vacuo to give2-ethyl-4-(4-methoxybenzyloxy)-1H-benzimidazole (900 mg) as pale yellowpowder.

mp: 73.8-77.9° C.

NMR (CDCl₃, δ): 1.40 (3H, t, J=7.5 Hz), 2.91 (2H, q, J=7.5 Hz), 3.82(3H, br s), 5.00-5.35 (2H, m), 6.57-7.20 (4H, m), 7.26-7.43 (1H, m),7.38 (2H, d, J=9 Hz), 9.11-9.52 (1H, m)

(4) A solution of 2-ethyl-4-(4-methoxybenzyloxy)-1H-benzimidazole (282mg), ethyl bromoacetate (184 mg) and potassium carbonate (414 mg) indimethylformamide (3 ml) was stirred for 2 hours, and to the reactionmixture were added ethyl acetate and water. The separated organic layerwas washed with brine, dried over magnesium sulfate and evaporated invacuo. The residue was purified by flash chromatography (ethylacetate:n-hexane=1:2 to 2:1, v/v) to give1-ethoxycarbonylmethyl-2-ethyl-4-(4-methoxybenzyloxy)-1H-benzimidazole(245 mg) as white powder.

mp: 112.1° C.

NMR (CDCl₃, δ): 1.25 (3H, t, J=7.5 Hz), 1.42 (3H, t, J=7.5 Hz), 2.86(2H, q, J=7.5 Hz), 3.80 (3H, s), 4.20 (2H, q, J=7.5 Hz), 4.78 (2H, s),5.30 (2H, s), 6.18 (1H, d, J=7.5 Hz), 6.29 (1H, d, J=7.5 Hz), 6.38 (2H,d, J=9 Hz), 7.08 (1H, t, J=7.5 Hz), 7.42 (2H, d, J=9 Hz)

(5) 1-Ethoxycarbonylmethyl-2-ethyl-4-hydroxy-1H-benzimidazole wasobtained according to a similar manner to that of Preparation 11.

mp: 148.2-150.5° C.

NMR (CDCl₃, δ): 1.25 (3H, t, J=7.5 Hz), 1.36 (3H, t, J=7.5 Hz), 2.90(2H, q, J=7.5 Hz), 4.22 (2H, q, J=7.5 Hz), 4.78 (2H, s), 6.73 (1H, d,J=8 Hz), 6.79 (1H, d, J=8 Hz), 7.14 (1H, t, J=8 Hz)

Preparation 15

(1) To a mixture of 3-benzyloxy-N-methyl-2-nitroaniline (453.3 mg), 80%methanol (6.8 ml), anhydrous ferric chloride (13.6 mg) and carbon (13.6mg) was dropwise added hydrazine monohydrate (255.6 μl), and the mixturewas stirred for 5 hours at ambient temperature. Insoluble material wasfiltered off, and the filtrate was concentrated in vacuo. To the residuewere added ethyl acetate and saturated sodium bicarbonate solution, andthe separated organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo. The residue was purified bysilica gel column chromatography (ethyl acetate-n-hexane) to give2-amino-3-benzyloxy-N-methylaniline (348.9 mg).

mp: 79-81° C.

NMR (CDCl₃, δ): 2.87 (3H, s), 3.43 (3H, br s), 5.07 (2H, s), 6.40 (1H,d, J=7.5 Hz), 6.49 (1H, d, J=7.5 Hz), 6.80 (1H, t, J=7.5 Hz), 7.29-7.47(5H, m)

(2) To a solution of 2-amino-3-benzyloxy-N-methylaniline (318.5 mg) inacetic acid (3.2 ml) was added tetramethyl orthocarbonate (233 μl) atambient temperature, and the mixture was stirred for 4 hours. Thereaction mixture was concentrated in vacuo, and to the residue wereadded ethyl acetate and saturated sodium bicarbonate solution. Theseparated organic layer was washed with water and brine, and dried overmagnesium sulfate. The solvent was removed in vacuo to give4-benzyloxy-2-methoxy-1-methyl-1H-benzimidazole (273.3 mg).

mp: 98-102° C.

NMR (CDCl₃, δ): 3.53 (3H, s), 4.22 (3H, s), 5.40 (2H, s), 6.63 (1H, d,J=7.5 Hz), 6.77 (1H, d, J=7.5 Hz), 6.99 (1H, t, J=7.5 Hz), 7.22-7.41(3H, m), 7.45-7.52 (2H, m)

(3) 4-Hydroxy-2-methoxy-1-methyl-1H-benzimidazole was obtained accordingto a similar manner to that of Preparation 11.

mp: 226-229° C.

NMR (DMSO-d₆, δ): 3.48 (3H, s), 4.08 (3H, s), 6.49 (1H, d, J=7.5 Hz),6.76 (1H, d, J=7.5 Hz), 6.88 (1H, t, J=7.5 Hz), 9.39 (1H, br s)

Preparation 16

(1)3-(N-Glycyl-N-methylamino)-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichlorobenzenewas obtained from1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-[N-methyl-N-(phthalimidoacetyl)amino]benzeneaccording to a similar manner to that of Example 3.

NMR (CDCl₃, δ): 1.05 (9H, s), 2.94 (1H, d, J=17 Hz), 3.09 (1H, d, J=17Hz), 3.20 (3H, s), 4.93 (2H, s), 7.18 (1H, d, J=8 Hz), 7.35-7.49 (7H,m), 6.69-7.77 (4H, m)

(2)1-(tert-Butyldiphenylsilyloxymethyl)-2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzenewas obtained by reacting3-(N-glycyl-N-methylamino)-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichlorobenzenewith 4-(methylcarbamoyl)cinnamic acid according to a similar manner tothat of Example 7.

mp: 219-222° C.

NMR (CDCl₃, δ): 1.05 (9H, s), 3.02 (3H, d, J=5 Hz), 3.21 (3H, s), 3.56(1H, dd, J=17.4 Hz), 3.93 (1H, dd, J=17, 5 Hz), 4.91 (1H, d, J=10 Hz),4.98 (1H, d, J=10 Hz), 6.15 (1H, br d, J=5 Hz), 6.51 (1H, d, J=15 Hz),6.63 (1H, br s), 7.19-7.28 (2H, m), 7.32-7.48 (6H, m), 7.50-7.60 (3H,m), 7.68-7.78 (6H, m)

(3) To a suspension of1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)-cinnamoylglycyl]amino]benzene(17.6 g) in tetrahydrofuran (138 ml) was added 1M tetrabutylammoniumfluoride in tetrahydrofuran (38.4 ml) at ambient temperature. Thereaction mixture was stirred for 1 hour. The mixture was concentratedand diluted with dichloromethane. The organic layer was washed with 1Nhydrochloric acid, saturated sodium bicarbonate solution and water,dried over magnesium sulfate and evaporated in vacuo to give2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]-benzene(8.14 g).

mp: 207-211° C.

NMR (DMSO-d₆, δ): 2.79 (3H, d, J=5 Hz), 3.11 (3H, s), 3.47 (1H, dd,J=17, 4 Hz), 3.77 (1H, dd, J=17, 5 Hz), 4.74 (1H, d, J=5 Hz), 5.34 (1H,t, J=5 Hz), 6.87 (1H, d, J=15 Hz), 7.40 (1H, d, J=15 Hz), 7.59-7.68 (4H,m), 7.85 (2H, d, J=8 Hz), 8.29 (1H, t, J=5 Hz), 8.48 (1H, d, J=5 Hz)

(4) To a mixture of2,6-dichloro-1-hydroxymethyl-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzene(8.10 g) in dichloromethane (81 ml) were added triphenylphosphine (5.66g) and carbon tetrabromide (8.95 g) at 0° C. After 15 minutes, thereaction mixture was stirred at ambient temperature for 3 hours. To themixture were added triphenylphosphine (1.42 g) and carbon tetrabromide(2.39 g) and stirred for another 2 hours. The reaction mixture waswashed with saturated sodium hydrogen carbonate, water and brine. Afterdried over anhydrous magnesium sulfate, the mixture was evaporated invacuo. The residue was purified by flash column chromatography followedby crystallizing from ethyl acetate to give2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzylbromide (6.40 g) as pale yellow crystals.

mp: 211.6-216.5° C.

NMR (CDCl₃, δ): 3.02 (3H, d, J=5 Hz), 3.27 (3H, s), 3.62 (1H, dd, J=17,4 Hz), 3.92 (1H, dd, J=17, 5 Hz), 4.78 (1.2H, s), 4.90 (0.8H, s), 6.15(1H, br d, J=5 Hz), 6.51 (1H, d, J=15 Hz), 6.67 (1H, br t, J=5 Hz), 7.29(1H, overlapped with H₂ O), 7.45-7.62 (4H, m), 7.76 (2H, d, J=8 Hz)

Preparation 17

(1) To a mixture of 2,6-dimethylbenzyl alcohol (17.1 g) and aceticanhydride (14.2 ml) was added 4-dimethylaminopyridine (17 mg), and themixture was stirred at 70° C. for 5 hours. After cooling, the mixturewas concentrated in vacuo, and ethyl acetate was added to the residue.The solution was washed with water, dried over magnesium sulfate andevaporated in vacuo to give 2,6-dimethylbenzyl acetate (22.5 g) ascolorless oil.

NMR (CDCl₃, δ): 2.07 (3H, s), 2.38 (6H, s), 5.19 (2H, s), 7.05 (2H, d,J=8 Hz), 7.15 (1H, t, J=8 Hz)

(2) To a solution of acetic anhydride (70 ml) and acetic acid (35 ml)was added cupric nitrate trihydrate (34.2 g) under ice-cooling, and asolution of 2,6-dimethylbenzyl acetate (21.0 g) in acetic anhydride (21ml) and acetic acid (10 ml) was dropwise added thereto over the periodof 30 minutes with stirring. The mixture was stirred for 30 minutes atthe same temperature and then for 30 minutes at ambient temperature. Thereaction mixture was poured into ice water, and extracted with ethylacetate. The organic layer was washed with water and brine, dried overmagnesium sulfate and evaporated in vacuo to give 2,6-dimethyl3-nitrobenzyl acetate (26.9 g) as pale yellow oil.

NMR (CDCl₃, δ): 2.08 (3H, s), 2.47 (3H, s), 2.50 (3H, s), 5.22 (2H, s),7.18 (1H, d, J=8 Hz), 7.69 (1H, d, J=8 Hz)

(3) To a solution of 2,6-dimethyl-3-nitrobenzyl acetate (26.9 g) inmethanol (266 ml) was added 1N sodium hydroxide solution (133 ml) atambient temperature, and the mixture was stirred for 30 minutes. To thereaction mixture was added water, and the resulting precipitates werecollected by filtration to give 2,6-dimethyl-3-nitrobenzyl alcohol (18.0g) as pale yellow crystals.

mp: 99-102° C.

NMR (CDCl₃, δ): 1.44 (1H, t, J=5 Hz), 2.50 (3H, s), 2.56 (3H, s), 4.82(2H, d, J=5 Hz), 7.17 (1H, d, J=8 Hz), 7.66 (1H, d, J=8 Hz)

(4) To a solution of tert-butyldiphenylsilyl chloride (30.7 g) indimethylformamide (90 ml) was added 2,6-dimethyl-3-nitrobenzyl alcohol(18.4 g), and imidazole (8.99 g) was added thereto under ice-cooling.The mixture was stirred for 15 minutes at the same temperature and thenfor 3 hours at ambient temperature. The reaction mixture was poured intoice water, and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over magnesium sulfate and evaporatedin vacuo to give1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-nitrobenzene (46.67g) as pale yellow oil.

NMR (CDCl₃, δ): 1.03 (9H, s), 2.20 (3H, s), 2.38 (3H, s), 5.73 (2H, s),7.06 (1H, d, J=8 Hz), 7.33-7.49 (6H, m), 7.58-7.73 (5H, m)

(5) To a suspension of1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-nitrobenzene (42 g)and ammonium chloride (4.2 g) in ethanol (378 ml)-water (42 ml) wasadded iron (7.0 g), and the mixture was refluxed for 6 hours, duringwhich iron (7.0 g) was added thereto twice. Insoluble materials werefiltered off, and the filtrate was concentrated. To the residue wasadded water and extracted with ethyl acetate. The organic layer waswashed with water and brine, dried over magnesium sulfate andconcentrated to give3-amino-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethylbenzene (42.8g) as pale yellow oil.

NMR (CDCl₃, δ): 1.04 (9H, s), 2.09 (3H, s), 2.11 (3H, s), 3.48 (2H, brs), 4.70 (2H, s), 6.58 (1H, d, J=8 Hz), 6.71 (1H, d, J=8 Hz), 7.33-7.48(6H, m), 7.66-7.73 (4H, m)

(6) To a suspension of3-amino-1-(tert-butyldiphenyl-silyloxymethyl)-2,6-dimethylbenzene (42.4g) in pyridine (17.2 g) and dimethylformamide (212 ml) was dropwiseadded phthalimidoacetyl chloride (25.6 g) over the period of 15 minutesunder ice-cooling, and the mixture was stirred for 1 hour at the sametemperature. To the reaction mixture was added water, and the resultingprecipitates were collected by filtration and washed with acetonitrileto give1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-(phthalimidoacetylamino)benzene(59.1 g) as colorless crystals.

mp: 207-210° C.

NMR (CDCl₃, δ): 1.02 (9H, s), 2.12 (3H, s), 2.19 (3H, s), 4.52 (2H, s),4.70 (2H, s), 6.95 (1H, d, J=8 Hz), 7.25-7.50 (7H, m), 7.63-7.80 (6H,m), 7.86-7.96 (2H, m)

(7) To a suspension of1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-(phthalimidoacetylamino)benzene(57.4 g) and sodium hydride (4.78 g) in dimethylformamide (287 ml) wasdropwise added methyl iodide (15.5 g) under ice-cooling, and the mixturewas stirred for 15 minutes at the same temperature and then for 2 hoursat ambient temperature. Water and ethyl acetate were added to thereaction mixture, and the resulting precipitates were collected byfiltration and washed with water and ethyl acetate to give1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-[N-methyl-N-(phthalimidoacetyl)amino]benzene(28.18 g) as colorless crystals.

mp: 180-182° C.

NMR (CDCl₃, δ): 1.04 (9H, s), 2.21 (3H, s), 2.27 (3H, s), 3.17 (3H, s),3.82 (1H, d, J=17 Hz), 4.12 (1H, d, J=17 Hz), 4.78 (2H, s), 7.09 (1H, d,J=8 Hz), 7.15 (1H, d, J=8 Hz), 7.34-7.49 (6H, m), 7.65-7.73 (6H, m),7.80-7.88 (2H, m)

(8)1-(tert-Butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-(N-glycyl-N-methylamino)benzenewas obtained according to a similar manner to that of Example 3.

NMR (CDCl₃, δ) 1.03 (9H, s), 2.02 (3H, s), 2.22 (3H, s), 2.82 (1H, d,J=17 Hz), 3.09 (1H, d, J=17 Hz), 3.15 (3H, s), 4.72 (2H, s), 6.92 (1H,d, J=8 Hz), 7.01 (1H, d, J=8 Hz), 7.32-7.49 (6H, m), 7.62-7.70 (4H, m)

(9)3-[N-[(E)-3-(6-Acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethylbenzenewas obtained by reacting1-(tert-butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-(N-glycyl-N-methylamino)benzenewith (E)-3-(6-acetylaminopyridin-3-yl)acrylic acid according to asimilar manner to that of Example 7.

mp: 200-202° C.

NMR (CDCl₃, δ): 1.05 (9H, s), 2.04 (3H, s), 2.21 (3H, s), 2.26 (3H, s),3.20 (3H, s), 3.52 (1H, dd, J=17, 5 Hz), 3.87 (1H, dd, J=17, 5 Hz), 4.73(2H, s), 6.45 (1H, d, J=15 Hz), 6.69 (1H, br t, J=5 Hz), 6.98 (1H, d,J=8 Hz), 7.07 (1H, d, J=8 Hz), 7.35-7.47 (6H, m), 7.64-7.71 (4H, m),7.84 (1H, dd, J=8, 3 Hz), 8.06 (1H, br s), 8.21 (1H, br d, J=8 Hz), 8.35(1H, br s)

(10)3-[N-[(E)-3-(6-Acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-1-hydroxymethyl-2,6-dimethylbenzenewas obtained according to a similar manner to that of Preparation16-(3).

mp: 215-216° C.

NMR (CDCl₃, δ) 1.64 (1H, t, J=5 Hz), 2.21 (3H, s), 2.30 (3H, s), 2.48(3H, s), 3.24 (3H, s), 3.62 (1H, dd, J=17, 5 Hz), 3.82 (1H, dd, J=17, 5Hz), 4.78 (2H, d, J=5 Hz), 6.45 (1H, d, J=15 Hz), 6.75 (1H, br t, J=5Hz), 7.01 (1H, d, J=8 Hz), 7.12 (1H, d, J=8 Hz), 7.50 (1H, d, J=15 Hz),7.84 (1H, dd, J=8, 2 Hz), 8.13 (1H, br s), 8.21 (1H, br d, J=8 Hz), 8.35(1H, d, J=2 Hz)

(11)3-[N-[(E)-3-(6-Acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethylbenzylbromide was obtained according to a similar manner to that ofPreparation 16-(4).

NMR (CDCl₃, δ): 2.22 (3H, s), 2.28 (3H, s), 2.46 (3H, s), 3.25 (3H, s),3.60 (1H, dd, J=17, 5 Hz), 3.82 (1H, dd, J=17, 4 Hz), 4.55 (2H, s), 6,46(1H, d, J=15 Hz), 6.71 (1H, br s), 7.03 (1H, d, J=8 Hz), 7.13 (1H, d,J=8 Hz), 7.51 (1H, d, J=15 Hz), 7.84 (1H, dd, J=8, 2 Hz), 8.13 (1H, brs), 8.22 (1H, br d, J=8 Hz), 8.36 (1H, d, J=2 Hz)

Preparation 18

To a solution of3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-1-hydroxymethyl-2,6-dimethylbenzene(69 mg) and triethylamine (20.4 mg) in dichloromethane (4.2 ml) wasadded mesyl chloride (21.2 mg) under ice-cooling, and the mixture wasstirred for 10 minutes at the same temperature and then for 75 minutesat ambient temperature. The reaction mixture was washed with water andsaturated sodium bicarbonate solution, and dried over magnesium sulfate.The solvent was removed in vacuo to give a mixture of3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethylbenzylchloride and3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethyl-1-(methylsulfonyloxymethyl)benzene.

Preparation 19

To a solution of3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-1-hydroxymethyl-2,6-dimethylbenzene(200 mg) in dimethylformamide (2 ml) were added triethylamine (136.1 μl)and mesyl chloride (52.9 μl) at 0° C., and the mixture was stirred for 1hour at the same temperature and then for 1 hour at ambient temperature.Chloroform and saturated sodium bicarbonate solution were added to thereaction mixture, and the separated organic layer was washed with water,saturated sodium bicarbonate solution and brine, and dried overmagnesium sulfate. The solvent was removed in vacuo to give3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethylbenzylchloride (191.0 mg) as pale yellow solid.

mp: 217.5-220.5° C.

NMR (DMSO-d₆, δ): 2.11 (3H, s), 2.28 (3H, s), 2.43 (3H, s), 3.09 (3H,s), 3.41 (1H, dd, J=16.5, 5.5 Hz), 3.60 (1H, dd, J=16.5, 5.5 Hz), 4.84(2H, s), 6.76 (1H, d, J=15.0 Hz), 7.21 (1H, d, J=8.5 Hz), 7.27 (1H, d,J=8.5 Hz), 7.37 (1H, d, J=15.0 Hz), 7.98 (1H, dd, J=8.5, 1.5 Hz), 8.11(1H, d, J=8.5 Hz), 8.17 (1H, t, J=,5.5 Hz), 8.47 (1H, d, J=1.5 Hz)

Preparation 20

(1)1-(tert-Butyldiphenylsilyloxymethyl)-2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzenewas obtained by reacting1-(tert-butyldiphenylsilyloxy-methyl)-2,6-dimethyl-3-(N-glycyl-N-methylamino)benzenewith 4-(methylcarbamoyl)cinnamic acid according to a similar manner tothat of Example 7.

mp: 204-208° C.

NMR (CDCl₃, δ) 1.05 (9H, s), 2.05 (3H, s), 2.26 (3H, s), 3.02 (3H, d,J=5 Hz), 3.20 (3H, s), 3.52 (1H, dd, J=17, 5 Hz), 3.87 (1H, dd, J=17, 5Hz), 4.73 (2H, s), 6.16 (1H, br d, J=5 Hz), 6.51 (1H, d, J=15 Hz), 6.69(1H, br t, J=5 Hz), 6.98 (1H, d, J=8 Hz), 7.06 (1H, d, J=8 Hz),7.35-7.48 (6H, m), 7.51-7.60 (3H, m), 7.65-7.80 (6H, m)

(2)1-Hydroxymethyl-2,6-dimethyl-3-[N-[4-(methylcarbamoyl)-cinnamoylglycyl]-N-methylamino]benzenewas obtained according to a similar manner to that of Preparation16-(3).

mp: 261-263° C.

NMR (DMSO-d₆, δ) 2.27 (3H, s), 2.40 (3H, s), 2.79 (3H, d, J=5 Hz), 3.08(3H, s), 3.43 (1H, dd, J=17, 5 Hz), 3.65 (1H, dd, J=17, 5 Hz), 4.53 (2H,d, J=5 Hz), 4.88 (1H, t, J=5 Hz), 6.89 (1H, d, J=15 Hz), 7.15 (2H, s),7.41 (1H, d, J=15 Hz), 7.64 (2H, d, J=8 Hz), 7.85 (2H, d, J=8 Hz), 8.21(1H, br t, J=5 Hz), 8.48 (1H, br d, J=8 Hz)

(3) 2,6-Dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyl chloride was obtained according toa similar manner to that of Preparation 19.

mp: 232° C.

NMR (CDCl₃, δ): 2.29 (3H, s), 2.46 (3H, s), 3.03 (3H, d, J=5 Hz), 3.24(3H, s), 3.59 (1H, d, J=17, 5 Hz), 3.82 (1H, dd, J=17, 4 Hz), 4.67 (2H,s), 6.20 (1H, m), 6.50 (1H, d, J=15 Hz), 6.70 (1H, d, J=5 Hz), 7.04 (1H,d, J=9 Hz), 7.14 (1H, d, J=9 Hz), 7.50-7.60 (3H, m), 7.75 (2H, d, J=9Hz)

Example 9

(1) To a solution of1-ethoxycarbonylmethyl-2-ethyl-4-hydroxy-1H-benzimidazole (140 mg) and2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzylbromide (289 mg) in dimethylformamide (3 ml) was added potassiumcarbonate (117 mg) under ice-cooling, and the mixture was stirred for 30minutes at the same temperature and then for 2 hours at ambienttemperature. To the reaction mixture was added saturated sodiumbicarbonate solution, and the mixture was extracted with ethyl acetate.The organic layer was dried over magnesium sulfate, and concentrated invacuo. The residue was purified by silica gel flash chromatography (5%methanol-ethyl acetate) and pulverized with diisopropyl ether to give4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-1-ethoxycarbonylmethyl-2-ethyl-1H-benzimidazole(317 mg) as pale yellow solid.

NMR (CDCl₃, δ): 1.26 (3H, t, J=7.5 Hz), 1.34 (3H, t, J=7.5 Hz), 2.86(2H, q, J=7.5 Hz), 3.00 (3H, d, J=5 Hz), 3.25 (3H, s), 3.66 (1H, dd,J=17, 4 Hz), 3.92 (1H, dd, J=17, 5 Hz), 4.22 (2H, q, J=7.5 Hz), 4.80(2H, s), 5.57 (1H, d, J=9 Hz), 5.61 (1H, d, J=9 Hz), 6.26 (1H, br q, J=5Hz), 6.53 (1H, d, J=15 Hz), 6.70 (1H, dd, J=5, 4 Hz), 6.85 (1H, d, J=8Hz), 6.89 (1H, d, J=8 Hz), 7.19 (1H, t, J=8 Hz), 7.29 (1H, d, J=8 Hz),7.46 (1H, d, J=8 Hz), 7.52 (2H, d, J=9 Hz), 7.57 (1H, d, J=15 Hz), 7.74(2H, d, J=9 Hz)

Example 10

To a solution of4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-1-ethoxycarbonylmethyl-2-ethyl-1H-benzimidazole(270 mg) in ethanol (3 ml) was added 1N sodium hydroxide solution (0.44ml), and the mixture was stirred for 2 hours at ambient temperature. Thereaction mixture was acidified with 1N hydrochloric acid, and thesolvent was removed in vacuo. The residue was pulverized with 99%acetonitrile to give1-carboxymethyl-4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-2-ethyl-1H-benzimidazole(280 mg) as pale yellow solid.

NMR (DMSO-d₆, δ): 1.26 (3H, t, J=7.5 Hz), 2.78 (3H, d, J=5 Hz), 3.15(3H, s), 3.34 (2H, overlapped with H₂ O), 3.54 (1H, dd, J=17, 5 Hz),3.83 (1H, dd, J=17, 4 Hz), 5.16 (2H, br s), 5.55 (2H, s), 6.87 (1H, d,J=15 Hz), 7.24 (2H, br s), 7.43 (1H, d, J=15 Hz), 7.64 (2H, d, J=9 Hz),7.80 (1H, s), 7.88 (2H, d, J=9 Hz), 8.36 (1H, t, J=5 Hz), 8.52 (1H, q,J=5 Hz)

Example 11

(1) A solution of1-carboxymethyl-4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]-benzyloxy]-2-ethyl-1H-benzimidazole(60 mg), dimethylamine hydrochloride (11.2 mg),1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (17.1 mg) and1-hydroxybenzotriazole (18.6 mg) in dimethylformamide (1 ml) was stirredfor 1 day at ambient temperature. To the reaction mixture was addedwater, and the mixture was extracted with chloroform. The organic layerwas washed with saturated sodium bicarbonate solution, dried overmagnesium sulfate, and concentrated in vacuo. The residue was purifiedby preparative thin layer chromatography (10% methanol-chloroform) togive4-[2,6-dichloro-3-[N-methyl-N-[4-(methyl-carbamoyl)cinnamoylglycyl]amino]-benzyloxy]-2-ethyl-1-dimethylcarbamoylmethyl-1H-benzimidazole(46 mg) as amorphous.

NMR (CDCl₃, δ): 1.34 (3H, t, J=7.5 Hz), 2.78 (2H, q, J=7.5 Hz), 2.98(3H, d, J=5 Hz), 3.01 (3H, s), 3.15 (3H, s), 3.25 (3H, s), 3.67 (1H, dd,J=15, 4 Hz), 3.92 (1H, d, J=15, 5 Hz), 4.85 (2H, s), 5.59 (2H, s), 6.47(1H, m), 6.53 (1H, d, J=15 Hz), 6.82 (2H, d, J=8 Hz), 6.85 (1H, m), 7.16(1H, t, J=8 Hz), 7.28 (1H, d, J=9 Hz), 7.43 (1H, d, J=9 Hz), 7.49 (2H,d, J=9 Hz), 7.54 (1H, d, J=15 Hz), 7.70 (2H, d, J=9 Hz)

its hydrochloride

NMR (CDCl₃ --CD₃ OD, δ): 1.34-1.54 (3H, m), 2.97 (3H, s), 3.02 (3H, s),3.07-3.30 (2H, m), 3.28 (3H, s), 3.31 (3H, s), 3.80 (1H, d, J=15 Hz),3.88 (1H, d, J=15 Hz), 5.44-5.69 (2H, m), 5.50 (1H, d, J=9 Hz), 5.60(1H, d, J=9 Hz), 6.64 (1H d, J=15 Hz), 7.13 (1H, d, J=9 Hz), 7.27 (1H,d, J=9 Hz), 7.44-7.58 (5H, m), 7.60 (1H, d, J=9 Hz), 7.80 (2H, d, J=9Hz)

Example 12

1-Allylcarbamoylmethyl-4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-2-ethyl-1H-benzimidazolewas obtained from1-carboxymethyl-4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]-amino]benzyloxy]-2-ethyl-1H-benzimidazole andallylamine according to a similar manner to that of Example 11.

NMR (CDCl₃, δ) 1.33 (3H, t, J=7.5 Hz), 2.84 (2H, q, J=7.5 Hz), 3.00 (3H,d, J=5 Hz), 3.28 (3H, s), 3.67 (1H, dd, J=15, 4 Hz), 3.80 (2H, br t, J=5Hz), 3.91 (1H, dd, J=15, 5 Hz), 4.78 (2H, s), 5.00 (1H, br d, J=17 Hz),5.05 (1H, br d, J=10 Hz), 5.58-5.76 (2H, m), 5.60 (2H, s), 6.15 (1H, m),6.53 (1H, d, J=15 Hz), 6.67 (1H, m), 6.92 (1H, d, J=9 Hz), 6.95 (1H, d,J=9 Hz), 7.24 (1H, t, J=9 Hz), 7.31 (1H, d, J=9 Hz), 7.50 (1H, d, J=9Hz), 7.54 (2H, d, J=9 Hz), 7.57 (1H, d, J=17 Hz), 7.74 (2H, d, J=9 Hz)

Example 13

2-Methoxy-1-methyl-4-[2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-1H-benzimidazole was obtained from4-hydroxy-2-methoxy-1-methyl-1H-benzimidazole and2,6-dichloro-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyl bromide according to a similar manner tothat of Example 9.

mp: 244-249° C.

NMR (CDCl₃, δ): 3.02 (3H, d, J=4.5 Hz), 3.27 (3H, s), 3.53 (3H, s), 3.67(1H, dd, J=16.5, 4.5 Hz), 3.93 (1H, dd, J=16.5, 4.5 Hz), 4.17 (3H, s),5.64 (2H, s), 6.29 (1H, q, J=4.5 Hz), 6.53 (1H, d, J=16.0 Hz), 6.70 (1H,t, J=4.5 Hz), 6.82-6.90 (2H, m), 7.11 (1H, t, J=8.5 Hz), 7.30 (1H, d,J=8.5 Hz), 7.46 (1H, d, J=8.5 Hz), 7.53 (2H, d, J=7.5 Hz), 7.58 (1H, d,J=16.0 Hz), 7.76 (2H, d, J=7.5 Hz)

Example 14

4-[3-[N-[(E)-3-(6-Acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethylbenzyloxy]-2-methoxy-1-methyl-1H-benzimidazolewas obtained from 4-hydroxy-2-methoxy-1-methyl-1H-benzimidazole and amixture of3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethyl-1-(methylsulfonyloxymethyl)benzeneand 3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethylbenzyl chloride according toa similar manner to that of Example 1.

NMR (CDCl₃, δ): 2.21 (3H, s), 2.33 (3H, s), 2.50 (3H, s), 3.26 (3H, s),3.54 (3H, s), 3.62 (1H, dd, J=17, 5 Hz), 3.88 (1H, dd, J=17, 5 Hz), 4.19(3H, s), 5.40 (2H, s), 6.47 (1H, d, J=15 Hz), 6.72 (1H, br t, J=5 Hz),6.81-6.89 (2H, m), 7.03-7.18 (3H, m), 7.51 (1H, d, J=15 Hz), 7.84 (1H,dd, J=8, 2 Hz), 8.11 (1H, br s), 7.21 (1H br d, J=8 Hz), 8.36 (1H, br s)

Example 15

The following compounds were obtained according to a similar manner tothat of Example 9.

(1)2-Methoxy-1-methyl-4-[3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]-2,6-dimethylbenzyloxy]-1H-benzimidazole

(2)4-[3-[N-[(E)-3-(6-Acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

(3)4-[3-[N-[(E)-3-(6-Acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-1,2-dimethyl-1H-benzimidazole

(4)4-[3-[N-Methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]-amino]-2,6-dimethylbenzyloxy]-1,2-dimethyl-1H-benzimidazole

(5)4-[3-[N-[(E)-3-(6-Acetylaminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethylbenzyloxy]-1,2-dimethyl-1H-benzimidazole

(6)4-(2,6-Dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-ethoxy-1-methyl-1H-benzimidazole

mp: 226-231° C.

NMR (CDCl₃, δ): 1.43 (3H, t, J=7.0 Hz), 2.32 (3H, s), 2.50 (3H, s), 3.00(3H, d, J=4.5 Hz), 3.24 (3H, s), 3.53 (3H, s), 3.61 (1H, dd, J=17.5, 4.5Hz), 3.87 (1H, dd, J=17.5, 4.5 Hz), 4.59 (2H, q, J=7.0 Hz), 5.41 (2H,s), 6.23 (1H, q, J=4.5 Hz), 6.52 (1H, d, J=15.0 Hz), 6.72 (1H, t, J=4.5Hz), 6.80-6.89 (2H, m), 7.02-7.17 (3H, m), 7.52 (2H, d, J=8.5 Hz), 7.56(1H, d, J=15.0 Hz), 7.74 (2H, d, J=8.5 Hz) (7)4-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dimethylbenzyloxy]-2-ethoxy-1-methyl-1H-benzimidazole

mp: 142.5-148.5° C.

NMR (CDCl₃, δ): 1.47 (3H, t, J=7.5 Hz), 2.22 (3H, s), 2.33 (3H, s), 2.50(3H, s), 3.25 (3H, s), 3.56 (3H, s), 3.64 (1H, dd, J=17.5, 4.5 Hz), 3.88(1H, dd, J=17.5, 4.5 Hz), 4.60 (2H, q, J=7.5 Hz), 5.42 (2H, s), 6.46(1H, d, J=15.0 Hz), 6.73 (1H, t, J=4.5 Hz), 6.81-6.90 (2H, m), 7.01-7.19(3H, m), 7.51 (1H, d, J=15.0 Hz), 7.84 (1H, dd, J=8.5, 1.5 Hz), 8.12(1H, d, J=1.5 Hz), 8.20 (1H, d, J=8.5 Hz), 8.36 (1H, d, J=1.5 Hz)

(8) 4-[2,6-Dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methoxymethyl-1-methyl-1H-benzimidazole

mp: 232-235° C.

NMR (DMSO-d₆, δ): 2.28 (3H, s), 2.40 (3H, s), 2.79 (3H, d, J=4.5 Hz),3.10 (3H, s), 3.28 (3H, s), 3.49 (1H, dd, J=16.5, 5.0 Hz), 3.67 (1H, dd,J=16.5, 5.0 Hz), 3.78 (3H, s), 4.63 (2H, s), 5.34 (2H, s), 6.87 (1H, d,J=15.5 Hz), 6.92 (1H, d, J=7.5 Hz), 7.13-7.33 (4H, m), 7.42 (1H, d,J=15.5 Hz), 7.62 (2H, d, J=8.5 Hz), 7.84 (2H, d, J=8.5 Hz), 8.26 (1H, t,J=5.0 Hz), 8.48 (1H, q, J=4.5 Hz)

its hydrochloride

mp: 225-233° C.

NMR (DMSO-d₆, δ): 2.29 (3H, s), 2.43 (3H, s), 2.79 (3H, d, J=4.5 Hz),3.12 (3H, s), 3.38 (3H, s), 3.50 (1H, dd, J=16.5, 6.0 Hz), 3.70 (1H, dd,J=16.5, 6.0 Hz), 3.98 (3H, s), 4.89 (2H, s), 5.37 (1H, d, J=10.0 Hz),5.44 (1H, d, J=10.0 Hz), 6.91 (1H, d, J=16.0 Hz), 7.27-7.46 (4H, m),7.50-7.68 (2H, m), 7.63 (2H, d, J=8.5 Hz), 7.87 (2H, d, J=8.5 Hz), 8.30(1H, t, J=6.0 Hz), 8.53 (1H, q, J=4.5 Hz)

(9)2-Acetyl-4-[2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-1-methyl-1H-benzimidazole

mp: 234-236° C.

NMR (DMSO-d₆, δ): 2.32 (3H, s), 2.45 (3H, s), 2.67 (3H, s), 2.79 (3H, d,J=4.5 Hz), 3.12 (3H, s), 3.50 (1H, dd, J=16.5, 5.5 Hz), 3.67 (1H, dd,J=16.5, 5.5 Hz), 4.04 (3H, s), 5.38 (2H, s), 6.88 (1H, d, J=16.0 Hz),7.08 (1H, d, J=7.5 Hz), 7.25-7.47 (5H, m), 7.63 (2H, d, J=8.5 Hz), 7.85(2H, d, J=8.5 Hz), 8.25 (1H, t, J=5.5 Hz), 8.47 (1H, q, J=4.5 Hz)

its hydrochloride

mp: 141-152° C.

NMR (DMSO-d₆, δ): 2.31 (3H, s), 2.43 (3H, s), 2.67 (3H, s), 2.78 (3H, d,J=4.5 Hz), 3.11 (3H, s), 3.50 (1H, dd, J=16.5, 5.5 Hz), 3.67 (1H, dd,J=16.5, 5.5 Hz), 4.04 (3H, s), 5.38 (2H, s), 6.88 (1H, d, J=16.0 Hz),7.08 (1H, d, J=7.5 Hz), 7.12-7.47 (5H, m), 7.63 (2H, d, J=8.5 Hz), 7.86(2H, d, J=8.5 Hz), 8.27 (1H, t, J=5.5 Hz), 8.50 (1H, q, J=4.5 Hz)

(10)4-[2,6-Dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-ethoxycarbonylmethyl-1-methyl-1H-benzimidazole

mp: 128-146° C.

NMR (DMSO-d₆, δ) 1.19 (3H, t, J=7.5 Hz), 2.29 (3H, s), 2.40 (3H, s),2.79 (3H, d, J=4.5 Hz), 3.12 (3H, s), 3.49 (1H, dd, J=16.5, 5.5 Hz),3.67 (1H, dd, J=16.5, 5.5 Hz), 3.72 (3H, s), 4.09 (2H, s), 4.11 (2H, q,J=7.5 Hz), 5.33 (2H, s), 6.89 (1H, d, J=16.0 Hz), 6.92 (1H, d, J=8.5Hz), 7.13-7.33 (4H, m), 7.42 (1H, d, J=16.0 Hz), 7.63 (2H, d, J=7.5 Hz),7.84 (2H, d, J=7.5 Hz), 8.25 (1H, t, J=5.5 Hz), 8.48 (1H, q, J=4.5 Hz)

(11)4-[2,6-Dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-1-methyl-2-dimethylamino-1H-benzimidazole

NMR (CDCl₃, δ): 2.34 (3H, s), 2.50 (3H, s), 2.95 (6H, s), 3.01 (3H, d,J=5 Hz), 3.23 (3H, s), 3.58-3.68 (4H, m), 3.88 (1H, dd, J=17, 5 Hz),5.42 (2H, s), 6.20 (1H, br d, J=5 Hz), 6.52 (1H, t, J=15 Hz), 6.72 (1H,br t, J=5 Hz), 6.80-6.90 (2H, m), 7.01-7.17 (3H, m), 7.50-7.60 (2H, m),7.75 (2H, d, J=8 Hz)

(12)4-[2,6-Dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-1-methyl-2-methylamino-1H-benzimidazole

NMR (CDCl₃ --CD₃ OD, δ): 2.29 (3H, s), 2.40 (3H, br s), 2.98 (3H, s),3.03 (3H, s), 3.22 (3H, s), 3.53 (3H, br s), 3.66 (1H, d, J=17 Hz), 3.87(1H, d, J=17 Hz), 5.27 (2H, br s), 6.57 (1H, d, J=15 Hz), 6.80-6.89 (2H,m), 7.06-7.16 (3H, m), 7.50-7.61 (3H, m), 7.75 (2H, d, J=8 Hz)

(13)4-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-isopropyl-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 1.41 (6H, d, J=7.5 Hz), 2.21 (3H, s), 3.13-3.30 (4H, m),3.60-3.75 (4H, m), 3.93 (1H, dd, J=4, 18 Hz), 5.69 (2H, s), 6.45 (1H, d,J=16 Hz), 6.70 (1H, t-like), 6.85 (1H, d, J=8 Hz), 6.97 (1H, d, J=8 Hz),7.19 (1H, t, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.41-7.56 (2H, m), 7.31 (1H,dd, J=2, 8 Hz), 8.03 (1H, s), 8.19 (8H, br d), 8.35 (1H, d, J=2 Hz)

(14)4-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-ethyl-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ) 1.36 (3H, t, J=7.5 Hz), 2.22 (3H, s), 2.92 (2H, q, J=7.5Hz), 3.28 (3H, s), 3.61-3.75 (4H, m), 3.93 (1H, dd, J=4, 18 Hz), 5.59(2H, s), 6.46 (1H, d, J=16 Hz), 6.65-6.72 (1H, m), 6.85 (1H, d, J=8 Hz),6.99 (1H, d, J=8 Hz), 7.22 (1H, t, J=8 Hz), 7.30 (1H, d, J=8 Hz),7.44-7.57 (2H, m), 7.83 (1H, dd, J=2, 8 Hz), 8.05 (1H, s), 8.20 (1H, brd, J=8 Hz), 8.35 (1H, s)

(15)4-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-pentafluoroethyl-1H-benzimidazole

NMR (CDCl₃, δ) 2.22 (3H, s), 3.26 (3H, s), 3.67 (1H, dd, J=4, 18 Hz),3.87-4.00 (4H, m), 5.73 (2H, s), 6.45 (1H, d, J=16 Hz), 6.64 (1H,t-like), 6.95 (1H, d, J=8 Hz), 7.10 (1H, d, J=8 Hz), 7.32 (1H, d, J=8Hz), 7.40 (1H, t, J=8 Hz), 7.45-7.57 (2H, m), 7.83 (1H, dd, J=2, 8 Hz),8.00 (1H, s), 8.20 (1H, br d, J=8 Hz), 8.35 (1H, s)

(16)9-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-3,4-dihydro-2H-[1,3]-oxazino[3,2-a]benzimidazole

NMR (CDCl₃, δ): 2.21 (3H, s), 2.28-2.38 (2H, m), 3.25 (3H, s), 3.65 (1H,dd, J=17, 4 Hz), 3.95 (1H, dd, J=17, 5 Hz), 4.10 (2H, br t, J=6 Hz),4.50 (2H, br t, J=6 Hz), 5.61 (2H, s), 6.46 (1H, d, J=15 Hz), 6.69 (1H,br s), 7.10 (1H, t, J=7.5 Hz), 7.29 (1H, d, J=7.5 Hz), 7.47 (1H, d,J=7.5 Hz), 7.51 (1H, d, J=15 Hz), 7.82 (1H, br d, J=7.5 Hz), 8.05 (1H,br s), 8.20 (1H, br d, J=7.5 Hz), 7.34 (1H, br s)

(17)7-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methylbenzoxazole

mp: 225-227° C.

NMR (CDCl₃, δ): 2.22 (3H, s), 2.65 (3H, s), 3.29 (3H, s), 3.67 (1H, dd,J=17, 4 Hz), 3.97 (1H, dd, J=17, 5 Hz), 5.52 (1H, d, J=10 Hz), 5.59 (1H,d, J=10 Hz), 6.46 (1H, d, J=15 Hz), 6.68 (1H, br s), 7.00 (1H, d, J=7.5Hz), 7.21-7.39 (3H, m), 7.51 (1H, br s), 7.56 (1H, d, J=5 Hz), 7.85 (1H,dd, J=7.5, 2 Hz), 8.06 (1H, br s), 8.22 (1H, br d, J=7.5 Hz), 7.36 (1H,d, J=2 Hz)

(18)7-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-3-methyl-2(3H)-benzoxazolone

NMR (CDCl₃, δ) 2.22 (3H, s), 3.28 (3H, s), 3.40 (3H, s), 3.63 (1H, dd,J=17, 4 Hz), 3.95 (1H, dd, J=17, 5 Hz), 5.50 (1H, d, J=10 Hz), 5.56 (1H,d, J=10 Hz), 6.46 (1H, d, J=15 Hz), 6.60-6.70 (2H, m), 6.88 (1H, d,J=7.5 Hz), 7.16 (1H, t, J=7.5 Hz), 7.34 (1H, d, J=7.5 Hz), 7.48-7.56(2H, m), 7.85 (1H, br d, J=7.5 Hz), 8.04 (1H, br s), 8.21 (1H, br d,J=7.5 Hz), 8.37 (1H, br s)

(19)7-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino-2,6-dichlorobenzyloxy]-3-ethoxycarbonylmethyl-2(3H)-benzoxazolone

NMR (CDCl₃, δ): 1.29 (3H, t, J=7.5 Hz), 2.21 (3H, s), 3.28 (3H, s), 3.63(1H, dd, J=17, 4 Hz), 3.94 (1H, dd, J=17, 5 Hz), 4.54 (2H, s), 5.51 (1H,d, J=10 Hz), 5.58 (1H, d, J=10 Hz), 6.45 (1H, d, J=15 Hz), 6.59 (1H, d,J=7.5 Hz), 6.67 (1H, br s), 6.90 (1H, d, J=7.5 Hz), 7.15 (1H, t, J=7.5Hz), 7.34 (1H, d, J=7.5 Hz), 7.49-7.57 (2H, m), 7.84 (1H, br d, J=7.5Hz), 8.07 (1H, br s), 8.21 (1H, br d, J=7.5 Hz), 8.36 (1H, br s)

(20)7-[2,6-Dichloro-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2,3-dimethylbenzofuran(from 7-hydroxy-2,3-dimethylbenzofuran and2,6-dichloro-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzylbromide)

mp: 237.2° C.

NMR (DMSO-d₆, δ): 2.10 (3H, s), 2.32 (3H, s), 2.77 (3H, d, J=5 Hz), 3.13(3H, s), 3.49 (1H, dd, J=17, 5 Hz), 3.76 (1H, dd, J=17, 4 Hz), 5.43 (2H,s), 6.85 (1H, d, J=15 Hz), 7.01 (1H, d, J=8 Hz), 7.05-7.18 (2H, m), 7.40(1H, d, J=15 Hz), 7.63 (2H, d, J=9 Hz), 7.73 (1H, d, J=9 Hz), 7.77 (1H,d, J=9 Hz), 7.85 (2H, d, J=9 Hz), 8.32 (1H, br t, J=5 Hz), 8.49 (1H, brq, J=5 Hz)

Preparation 21

4-Benzyloxy-2-ethoxy-1-methyl-1H-benzimidazole was obtained from3-benzyloxy-2-amino-N-methylaniline and tetraethylorthocarbonateaccording to a similar manner to that of Preparation 15-(2).

mp: 99-100° C.

NMR (CDCl₃, δ): 1.47 (3H, t, J=7.5 Hz), 3.51 (3H, s), 4.66 (2H, q, J=7.5Hz), 5.40 (2H, s), 6.61 (1H, d, J=8.5 Hz), 6.75 (1H, d, J=8.5 Hz), 6.97(1H, t, J=8.5 Hz), 7.22-7.38 (3H, m), 7.49 (2H, d, J=7.5 Hz)

Preparation 22

(1) To a mixture of 3-benzyloxy-2-nitro-N-methylaniline (400 mg) andN,N-dimethylaniline (1 ml) was added methoxyacetyl chloride (310 μl)under nitrogen atmosphere, and the mixture was stirred for 2.5 hours at90° C. After cooling, ethyl acetate was added to the reaction mixture,and the mixture was washed with water and brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by silica gelcolumn chromatography (ethyl acetate:n-hexane=2:1, v/v) to give3-benzyloxy-2-nitro-N-methoxyacetyl-N-methylaniline (474.2 mg).

mp: 111-112.5° C.

NMR (CDCl₃, δ): 3.20 (3H, s), 3.34 (3H, s), 3.79 (1H, d, J=15.0 Hz),3.87 (1H, d, J=15.0 Hz), 5.22 (2H, s), 6.89 (1H, d, J=8.5 Hz), 7.13 (1H,d, J=8.5 Hz), 7.29-7.42 (5H, m), 7.45 (1H, t, J=8.5 Hz)

(2) 4-Benzyloxy-2-methoxymethyl-1-methyl-1H-benzimidazole was obtainedaccording to a similar manner to that of Preparation 9.

mp: 120-122° C.

NMR (CDCl₃, δ): 3.38 (3H, s), 3.82 (3H, s), 4.78 (2H, s), 5.38 (2H, s),6.67 (1H, d, J=8.5 Hz), 6.93 (1H, d, J=8.5 Hz), 7.14 (1H, t, J=8.5 Hz),7.23-7.39 (3H, m), 7.51 (2H, d, J=8.5 Hz)

Preparation 23

(1) A mixture of 3-benzyloxy-2-amino-N-methylaniline (400 mg), lacticacid (473.8 mg) and 4N hydrochloric acid (1.6 ml) was refluxed for 1.5hours. After cooling, the mixture was adjusted to pH 8 with 28% ammoniasolution, and extracted with ethyl acetate. The organic layer was washedwith water and brine, dried over magnesium sulfate and evaporated invacuo. The residue was purified by silica gel column chromatography(ethyl acetate:n-hexane=2:1, v/v) to give4-benzyloxy-2-(1-hydroxyethyl)-1-methyl-1H-benzimidazole (96.2 mg).

mp: 148.5-150.5° C.

NMR (DMSO-d₆, δ): 1.57 (3H, d, J=7.0 Hz), 3.81 (3H, s), 5.03 (1H, quint,J=7.0 Hz), 5.33 (2H, s), 5.55 (1H, d, J=7.0 Hz), 6.77 (1H, dd, J=7.0,2.5 Hz), 7.07-7.14 (2H, m), 7.29-7.43 (3H, m), 7.50 (2H, d, J=7.0 Hz)

(2) To a solution of4-benzyloxy-2-(1-hydroxyethyl)-1-methyl-1H-benzimidazole (87.0 mg) indichloromethane (3 ml) was added manganese dioxide (870 mg) at 0° C.under nitrogen atmosphere, and the mixture was stirred for 30 minutes at0° C. and then for 1.5 hours at ambient temperature. The reactionmixture was purified by silica gel column chromatography (ethylacetate:n-hexane=3:1, v/v) to give2-acetyl-4-benzyloxy-1-methyl-1H-benzimidazole (74.2 mg).

mp: 102-103.5° C.

NMR (CDCl₃, δ): 2.88 (3H, s), 4.11 (3H, s), 5.46 (2H, s), 6.72 (1H, d,J=8.5 Hz), 7.00 (1H, d, J=8.5 Hz), 7.23-7.41 (4H, m), 7.52 (2H, d, J=7.5Hz)

Preparation 24

(1) 3-Benzyloxy-2-nitro-N-ethoxycarbonylacetyl-N-methylaniline wasobtained from 3-benzyloxy-2-nitro-N-methylaniline andethoxycarbonylacetyl chloride according to a similar manner to that ofPreparation 22-(1).

NMR (CDCl₃, δ): 1.24 (3H, t, J=7.5 Hz), 3.21 (3H, s), 3.23 (2H, m), 4.15(2H, m), 5.21 (2H, s), 6.99 (1H, d, J=7.5 Hz), 7.14 (1H, d, J=7.5 Hz),7.32-7.52 (6H, m)

(2) 4-Benzyloxy-2-ethoxycarbonylmethyl-1-methyl-1H-benzimidazole wasobtained according to a similar manner to that of Preparation 9.

mp: 105.5-106° C.

NMR (CDCl₃, δ): 1.28 (3H, t, J=7.0 Hz), 3.76 (3H, s), 4.06 (2H, s), 4.20(2H, q, J=7.0 Hz), 5.37 (2H, s), 6.69 (1H, d, J=7.5 Hz), 6.93 (1H, d,J=7.5 Hz), 7.13 (1H, t, J=7.5 Hz), 7.25-7.39 (3H, m), 7.50 (2H, d, J=7.5Hz)

Preparation 25

To a mixture of 3-benzyloxy-2-amino-N-methylaniline (200 mg) and methylisothiocyanate (70.5 mg) was added tetrahydrofuran (2 ml) at ambienttemperature, and the mixture was stirred for 2 days. The solvent wasremoved in vacuo, and the residue was dissolved in acetonitrile (2 ml).Methyl iodide (149 mg) was added thereto under ice-cooling, the mixturewas stirred for 5 hours. The reaction mixture was concentrated in vacuo,and the residue was crystallized with ethyl acetate and recrystallizedwith acetonitrile to give4-benzyloxy-1-methyl-2-methylamino-1H-benzimidazole (148 mg).

mp: 212.9° C.

NMR (CDCl₃ --CD₃ OD, δ): 3.12 (3H, s), 3.80 (3H, s), 5.20 (2H, s), 6.87(2H, d, J=7.5 Hz), 7.22 (1H, t, J=7.5 Hz), 7.34-7.51 (5H, m)

Preparation 26

To a solution of 4-benzyloxy-1-methyl-2-methylamino-1H-benzimidazole(200 mg) in dimethylformamide (2 ml) was added sodium hydride (32.9 mg)under ice-cooling, and the mixture was stirred for 15 minutes. To themixture was added methyl iodide (127 mg), and the mixture was stirredfor 15 minutes under ice-cooling and then for 2 hours at ambienttemperature. Water was added to the reaction mixture, and extracted withchloroform. The organic layer was dried over magnesium sulfate andevaporated in vacuo. The residue was purified by flash chromatography(chloroform:methanol=50:1, v/v) to give4-benzyloxy-1-methyl-2-dimethylamino-1H-benzimidazole (100 mg).

NMR (CDCl₃, δ): 2.99 (6H, s), 3.61 (3H, s), 5.40 (2H, s), 6.60 (1H, d,J=8 Hz), 6.79 (1H, d, J=8 Hz), 6.98 (1H, t, J=8 Hz), 7.29-7.43 (3H, m),7.50 (2H, d, J=8 Hz)

Preparation 27

A mixture of 3-benzyloxy-2-amino-N-methylaniline (600 mg), isobutyricacid (243 mg) and 4N hydrochloric acid (3.5 ml) was refluxed for 3hours, and the solvent was removed in vacuo. Chloroform and saturatedsodium bicarbonate solution were added to the residue. The separatedorganic layer was washed with water and brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by silica gelcolumn chromatography (chloroform:methanol=50:1, v/v) to give4-hydroxy-2-isopropyl-1-methyl-1H-benzimidazole (33 mg).

NMR (CDCl₃, δ): 1.40 (6H, d, J=7.5 Hz), 3.20 (1H, m), 3.71 (3H, s), 6.75(1H, d, J=8 Hz), 6.82 (1H, d, J=8 Hz), 7.13 (1H, t, J=8 Hz)

Preparation 28

(1) To a solution of 3-benzyloxy-2-amino-N-methylaniline (500 mg) andpentafluoropropionic acid (395 mg) in tetrahydrofuran (3 ml) was added2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (1.35 g), and the mixturewas stirred for 4 hours at 50° C. To the mixture was further added2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline (108 mg), and the mixturewas stirred for 20 hours. The reaction mixture was concentrated invacuo, and the residue was dissolved in ethyl acetate. The organic layerwas washed with water and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by silica gel columnchromatography to give a residue containing3-benzyloxy-2-pentafluoropropionamido-N-methylaniline and4-benzyloxy-2-pentafluoroethyl-1-methyl-1H-benzimidazole.

(2) To a solution of the residue obtained above (1) in dichloromethanewas added phosphorus pentachloride (291 mg), and the mixture wasrefluxed for 1 hour. The reaction mixture was washed with water andbrine, dried over magnesium sulfate and evaporated in vacuo. The residuewas purified by silica gel column chromatography (chloroform) to give4-benzyloxy-2-pentafluoroethyl-1-methyl-1H-benzimidazole (150 mg).

NMR (CDCl₃, δ): 3.92 (3H, s), 5.49 (2H, s), 6.75 (1H, d, J=8 Hz), 7.00(1H, d, J=8 Hz), 7.22-7.40 (4H, m), 7.49 (2H, d, J=8 Hz)

Preparation 29

(1) 3-Benzyloxy-2-nitro-N-tert-butoxycarbonyl-N-(2-methoxyethyl)anilinewas obtained from 3-benzyloxy-2-nitro-N-tert-butoxycarbonylaniline and2-methoxyethyl chloride according to a similar manner to that ofPreparation 3.

(2) 3-Benzyloxy-2-nitro-N-(2-methoxyethyl)aniline was obtained accordingto a similar manner to that of Preparation 5.

NMR (CDCl₃, δ): 3.35 (2H, q, J=6 Hz), 3.40 (3H, s), 3.61 (2H, t, J=6Hz), 5.16 (2H, s), 6.21 (1H, t-like), 6.30-6.42 (2H, m), 7.20 (1H, t,J=8 Hz), 7.27-7.47 (5H, m)

Preparation 30

(1) 3-Benzyloxy-2-nitro-N-tert-butoxycarbonyl-N-(3-hydroxypropyl)anilinewas obtained from 3-benzyloxy-2-nitro-N-tert-butoxycarbonylaniline and3-hydroxypropyl bromide according to a similar manner to that ofPreparation 3.

NMR (CDCl₃, δ): 1.35 (9H, br s), 1.68-1.81 (2H, m), 3.14 (1H, br s),3.55-3.72 (3H, m), 3.80 (1H, br s), 5.20 (2H, br s), 6.81 (1H, br d,J=7.5 Hz), 7.01 (1H, d, J=7.5 Hz), 7.29-7.40 (6H, m)

(2) 3-Benzyloxy-2-nitro-N-(3-hydroxypropyl)aniline was obtainedaccording to a similar manner to that of Preparation 5.

NMR (CDCl₃, δ): 1.43 (1H, t, J=6 Hz), 1.86-1.98 (2H, m), 3.15 (2H, q,J=6 Hz), 3.81 (2H, q, J=6 Hz), 5.15 (2H, br s), 6.28 (1H, br s), 6.32(1H, d, J=7.5 Hz), 6.42 (1H, d, J=7.5 Hz), 7.21 (1H, t, J=7.5 Hz),7.28-7.48 (5H, m)

(3) 2-Amino-3-benzyloxy-N-(3-hydroxypropyl)aniline was obtainedaccording to a similar manner to that of Preparation 14-(2).

mp: 82-83° C.

NMR (CDCl₃, δ): 1.87-1.99 (2H, m), 3.30 (2H, t, J=6 Hz), 3.46 (2H, brs), 3.84 (2H, t, J=6 Hz), 5.08 (2H, s), 6.41 (1H, d, J=7.5 Hz), 6.49(1H, d, J=7.5 Hz), 7.75 (1H, t, J=7.5 Hz), 7.28-7.47 (5H, m)

(4) To a solution of 2-amino-3-benzyloxy-N-(3-hydroxypropyl)aniline (100mg) in chloroform (2 ml) was added 1,1'-thiocarbonyldiimidazole (72.7mg) at ambient temperature, and the mixture was stirred for 2 hours atthe same temperature and refluxed for 5 hours. The reaction mixture waswashed with water and brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by preparative thin layerchromatography (chloroform:methanol=10:1, v/v) to give4-benzyloxy-1-(3-hydroxypropyl)-2-thioxo-2,3-dihydro-1H-benzimidazole(75 mg).

mp: 124-125° C.

NMR (CDCl₃, δ): 1.94-2.05 (2H, m), 3.48-3.58 (3H, m), 4.44 (2H, br t,J=6 Hz), 5.19 (2H, s), 6.79 (1H, d, J=7.5 Hz), 6.82 (1H, d, J=7.5 Hz),7.14 (1H, t, J=7.5 Hz), 7.33-7.46 (5H, m), 9.63 (1H, br s)

(5) To a solution of4-benzyloxy-1-(3-hydroxypropyl)-2-thioxo-2,3-dihydro-1H-benzimidazole(70 mg) in acetonitrile (2 ml) was added methyl iodide (37.9 mg), andthe mixture was stirred overnight. The reaction mixture was concentratedin vacuo. The residue was purified by preparative thin layerchromatography and pulverized with diisopropyl ether to give4-benzyloxy-1-(3-hydroxypropyl)-2-methylthio-1H-benzimidazole (67 mg).

mp: 106-107° C.

NMR (CDCl₃, δ): 1.99-2.10 (2H, m), 2.84 (3H, s), 3.59-3.68 (3H, m), 4.21(2H, t, J=7 Hz), 5.42 (2H, s), 6.67 (1H, d, J=7.5 Hz), 6.92 (1H, d,J=7.5 Hz), 7.05 (1H, t, J=7.5 Hz), 7.28-7.40 (3H, m), 7.50 (2H, br d,J=7.5 Hz)

(6) To a solution of4-benzyloxy-1-(3-hydroxypropyl)-2-methylthio-1H-benzimidazole (59 mg) indimethylformamide (1 ml) was added sodium hydride at ambienttemperature, and the mixture was stirred overnight. Water was added tothe reaction mixture, and extracted with ethyl acetate. The extract waswashed with water and brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by preparative thin layerchromatography (chloroform:methanol=10:1, v/v) and pulverized withdiisopropyl ether to give9-benzyloxy-3,4-dihydro-2H-[1,3]oxazino-[3,2-a]benzimidazole (43 mg).

mp: 183-184° C.

NMR (CDCl₃, δ): 2.28-2.38 (2H, m), 4.09 (2H, t, J=7.5 Hz), 4.51 (2H, t,J=6 Hz), 5.41 (2H, s), 6.73 (1H, d, J=7.5 Hz), 6.79 (1H, d, J=7.5 Hz),7.01 (1H, t, J=7.5 Hz), 7.23-7.38 (3H, m), 7.50 (2H, br d, J=7.5 Hz)

Preparation 31

(1) To a solution of 3-nitrobenzene-1,2-diol (600 mg) in methanol (6 ml)was added 10% palladium on carbon (60 mg), and the mixture was stirredfor 3 hours at ambient temperature under hydrogen atmosphere. Insolublematerial was filtered off, and the filtrate was concentrated in vacuo.The residue was crystallized with diisopropyl ether to give3-aminobenzene-1,2,-diol (470 mg).

mp: 163-166° C.

NMR (DMSO-d₆, δ): 4.30 (2H, br s), 6.01-6.13 (2H, m), 6.34 (1H, t, J=8Hz)

(2) 3-Aminobenzene-1,2-diol (450 mg) was dissolved in 10% hydrogenchloride-methanol solution (1 ml), and the solvent was removed. Theresidue was dissolved in ethanol, and acetamide (227 mg) was addedthereto. The mixture was heated at 180° C. for 2 hours. After cooling,chloroform and methanol were added thereto, and insoluble material wasfiltered off. The filtrate was washed with saturated sodium bicarbonatesolution, dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by flash chromatography (chloroform:methanol=40:1,v/v) to give 7-hydroxy-2-methylbenzoxazole (183 mg).

mp: 152-154° C.

NMR (CDCl₃, δ): 2.65 (3H, s), 6.41 (1H, br s), 6.85 (1H, d, J=7.5 Hz),7.16 (1H, t, J=7.5 Hz), 7.24 (1H, d, J=7.5 Hz)

Preparation 32

(1) To a solution of 3-nitrobenzene-1,2-diol (2.78 g) and3,4-dihydro-2H-pyrane (1.81 g) in benzene (39 ml) was addedp-toluenesulfonic acid monohydrate (5 mg) at ambient temperature, andthe mixture was stirred for 24 hours. The reaction mixture was washedwith saturated sodium bicarbonate solution, dried over magnesium sulfateand evaporated in vacuo. The residue was purified by silica gel columnchromatography (chloroform-methanol) and crystallized with n-hexane togive 2-nitro-6-(tetrahydropyran-2-yloxy)phenol (2.32 g).

mp: 72-75° C.

NMR (CDCl₃, δ): 1.59-1.80 (3H, m), 1.85-2.17 (3H, m), 3.62 (1H, dt,J=10, 4 Hz), 3.97 (1H, dt, J=10, 4 Hz), 5.48 (1H, t, J=4 Hz), 6.89 (1H,t, J=7.5 Hz), 7.43 (1H, d, J=7.5 Hz), 7.78 (1H, d, J=7.5 Hz)

(2) 2-Amino-6-(tetrahydropyran-2-yloxy)phenol was obtained according toa similar manner to that of Preparation 31-(1).

mp: 163-166° C.

NMR (CDCl₃, δ): 1.48-1.70 (3H, m), 1.77-2.02 (3H, m), 3.57-3.66 (1H, m),3.75 (2H, br s), 3.98-4.07 (1H, m), 5.08-5.13 (1H, m), 6.46 (1H, d,J=7.5 Hz), 6.50 (1H, d, J=7.5 Hz), 6.63 (1H, t, J=7.5 Hz), 6.70 (1H, brs)

(3) To a solution of 2-amino-6-(tetrahydropyran-2-yloxy)phenol (2.0 g)in anhydrous tetrahydrofuran (30 ml) was added 1,1'-carbonyldiimidazole(2.03 g), and the mixture was refluxed for 2 hours under nitrogenatmosphere. After cooling, the reaction mixture was concentrated invacuo. The residue was purified by flash chromatography(chloroform:methanol=40:1, v/v) and crystallized with diisopropyl etherto give 7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (1.96 g).

mp: 174-176° C.

NMR (CDCl₃, δ): 1.55-2.14 (6H, m), 3.58-3.68 (1H, m), 3.95 (1H, dt,J=10, 2 Hz), 5.63 (1H, br s), 6.71 (1H, d, J=7.5 Hz), 6.92 (1H, d, J=7.5Hz), 7.06 (1H, t, J=7.5 Hz), 8.49 (1H, br s)

(4) To a suspension of 7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone(300 mg) and potassium carbonate (529 mg) in dimethylformamide (3 ml)was added methyl iodide at ambient temperature, and the mixture wasstirred for 3 hours under nitrogen atmosphere. Water was added to thereaction mixture, and the resulting precipitates were collected byfiltration to give3-methyl-7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (299 mg).

mp: 128-129° C.

NMR (CDCl₃, δ): 1.57-1.78 (3H, m), 1.81-2.13 (3H, m), 3.39 (3H, s),3.58-3.67 (1H, m), 3.94 (1H, dt, J=10, 2 Hz), 5.64 (1H, br s), 6.62 (1H,d, J=7.5 Hz), 6.92 (1H, d, J=7.5 Hz), 7.09 (1H, t, J=7.5 Hz)

(5) To a suspension of3-methyl-7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone (280 mg) inmethanol (2.3 ml) was added 1N hydrochloric acid (0.5 ml) at ambienttemperature, and the mixture was stirred for 30 minutes. The reactionmixture was concentrated to 1/3 volume, and water was added thereto. Themixture was extracted with chloroform, and the extract was dried overmagnesium sulfate and concentrated in vacuo. The residue wascrystallized with diisopropyl ether to give7-hydroxy-3-methyl-2(3H)-benzoxazolone (164 mg).

mp: 209-211° C.

NMR (DMSO-d₆, δ) 3.30 (3H, s), 6.63 (1H, d, J=7.5 Hz), 6.68 (1H, d,J=7.5 Hz), 7.01 (1H, t, J=7.5 Hz)

Preparation 33

(1)3-Ethoxycarbonylmethyl-7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolonewas obtained from 7-(tetrahydropyran-2-yloxy)-2(3H)-benzoxazolone andethyl bromoacetate according to a similar manner to that of Preparation32-(4).

mp: 92-93° C.

NMR (CDCl₃, δ) 1.29 (3H, t, J=7.5 Hz), 1.53-1.79 (3H, m), 1.81-2.15 (3H,m), 3.59-3.69 (1H, m), 3.96 (1H, dt, J=10, 2 Hz), 4.26 (2H, q, J=7.5Hz), 4.53 (2H, s), 5.64 (1H, br s), 6.55 (1H, d, J=7.5 Hz), 6.95 (1H, d,J=7.5 Hz), 7.09 (1H, t, J=7.5 Hz)

(2) 3-Ethoxycarbonylmethyl-7-hydroxy-2(3H)-benzoxazolone was obtainedaccording to a similar manner to that of Preparation 32-(5).

mp: 150-152° C.

NMR (CDCl₃, δ) 1.29 (3H, t, J=7.5 Hz), 4.26 (2H, q, J=7.5 Hz), 4.54 (2H,s), 6.11 (1H, br s), 6.48 (1H, d, J=7.5 Hz), 6.75 (1H, d, J=7.5 Hz),7.05 (1H, t, J=7.5 Hz)

Preparation 34

The following compounds were obtained according to a similar manner tothat of Preparation 11.

(1) 2-Ethoxy-4-hydroxy-1-methyl-1H-benzimidazole

mp: 163.5-165° C.

NMR (CDCl₃, δ): 1.43 (3H, t, J=6.5 Hz), 3.51 (3H, s), 4.54 (2H, q, J=6.5Hz), 6.71 (2H, t, J=8.5 Hz), 7.03 (1H, t, J=8.5 Hz), 8.05 (1H, br s)

(2) 4-Hydroxy-2-methoxymethyl-1-methyl-1H-benzimidazole

mp: 162.5-163° C.

NMR (CDCl₃, δ): 3.33 (3H, s), 3.81 (3H, s), 4.81 (2H, s), 6.85 (1H, d,J=8.5 Hz), 6.87 (1H, d, J=8.5 Hz), 7.22 (1H, t, J=8.5 Hz)

(3) 2-Acetyl-4-hydroxy-1-methyl-1H-benzimidazole

mp: 154-155° C.

NMR (CDCl₃, δ): 2.80 (3H, s), 4.11 (3H, s), 6.83 (1H, d, J=8.5 Hz), 6.96(1H, d, J=8.5 Hz), 7.33 (1H, t, J=8.5 Hz)

(4) 2-Ethoxycarbonylmethyl-4-hydroxy-1-methyl-1H-benzimidazole

mp: 166.5-182° C.

NMR (CDCl₃, δ): 1.23 (3H, t, J=7.0 Hz), 3.72 (3H, s), 4.13 (2H, s), 4.17(2H, q, J=7.0 Hz), 6.81 (1H, d, J=8.5 Hz), 6.84 (1H, d, J=8.5 Hz), 7.19(1H, t, J=8.5 Hz)

(5) 2-Amino-3-hydroxy-N-methylaniline

mp: 94-97° C.

NMR (DMSO-d₆, δ): 2.68 (3H, d, J=4.5 Hz), 3.80 (2H, br s), 4.52 (1H, q,J=4.5 Hz), 5.98 (1H, d, J=8.5 Hz), 6.13 (1H, d, J=8.5 Hz), 6.38 (1H, t,J=8.5 Hz), 8.73 (1H, br s)

(6) 4-Hydroxy-1-methyl-2-dimethylamino-1H-benzimidazole

mp: 177-179° C.

NMR (CDCl₃, δ): 2.93 (6H, s), 3.60 (3H, s), 6.71 (2H, br d, J=8 Hz),7.03 (1H, t, J=8 Hz)

(7) 2-Pentafluoroethyl-4-hydroxy-1-methyl-1H-benzimidazole

NMR (CDCl₃ --CD₃ OD, δ): 3.93 (3H, s), 6.86 (1H, d, J=8 Hz), 6.98 (1H,d, J=8 Hz), 7.34 (1H, t, J=8 Hz)

(8) 2-Amino-3-hydroxy-N-(2-methoxyethyl)aniline

NMR (CDCl₃, δ): 3.24-3.35 (2H, m), 3.40 (3H, s), 3.64 (2H, t, J=6 Hz),6.25-6.37 (2H, m), 6.74 (1H, t, J=8 Hz)

(9) 2-Amino-3-hydroxy-N-ethylaniline (from3-benzyloxy-2-nitro-N-ethylaniline)

NMR (CDCl₃, δ): 1.30 (3H, t, J=7 Hz), 3.16 (2H, q, J=7 Hz), 6.29 (2H, d,J=8 Hz), 6.74 (1H, t, J=8 Hz)

Preparation 35

To a suspension of 4-benzyloxy-1-methyl-2-methylamino-1H-benzimidazole(150 mg) in dichloromethane (2 ml) was added boron tribromide-methylsulfide complex (211 mg) in dryice-aceton bath, and the mixture wasstirred for 1 hour under ice-cooling and then at ambient temperatureovernight. To the reaction mixture were added chloroform-methanol (3:1,v/v) and saturated sodium bicarbonate solution, and insoluble materialwas filtered off. The separated organic layer was concentrated in vacuo.The residue was purified by preparative thin layer chromatography(chloroform:methanol=8:1, v/v) to give4-hydroxy-1-methyl-2-methylamino-1H-benzimidazole (49 mg).

NMR (CDCl₃ --CD₃ OD, δ): 3.09 (3H, s), 3.48 (3H, s), 6.60 (1H, d, J=7.5Hz), 6.69 (1H, d, J=7.5 Hz), 6.98 (1H, t, J=7.5 Hz)

Preparation 36

(1) To a solution of sodium hydroxide (830 mg) in dimethylsulfoxide (100ml) was added (4-methoxycarbonylbenzyl)triphenylphosphonium bromide(10.0 g), and after 30 minutes, 4-pyridinecarbaldehyde (2.22 g) wasadded thereto under ice-cooling. The mixture was stirred overnight.Water was added to the reaction mixture, and extracted with ethylacetate. The organic layer was washed with water and brine, dried overmagnesium sulfate and concentrated in vacuo. The residue was purified byflash chromatography (n-hexane-ethyl acetate) to give methyl4-[(E)-2-(4-pyridyl)vinyl]benzoate (1.18 g) and methyl4-[(Z)-2-(4-pyridyl)vinyl]benzoate (2.67 g).

Methyl 4-[(E)-2-(4-pyridyl)vinyl]benzoate

mp: 152-154° C.

NMR (CDCl₃, δ): 3.93 (3H, s), 7.11 (1H, d, J=16 Hz), 7.32 (1H, d, J=16Hz), 7.39 (2H, d, J=6 Hz), 7.60 (2H, d, J=7.5 Hz), 8.06 (2H, d, J=7.5Hz), 8.61 (2H, d, J=6 Hz)

Methyl 4-[(Z)-2-(4-pyridyl)vinyl]benzoate

NMR (CDCl₃, δ): 3.90 (3H, s), 6.61 (1H, d, J=12 Hz), 6.82 (1H, d, J=12Hz), 7.08 (2H, d, J=6 Hz), 7.28 (2H, d, J=7.5 Hz), 7.93 (2H, d, J=7.5Hz), 8.48 (2H, d, J=6 Hz)

(2) To a suspension of lithium aluminum hydride (92.8 mg) intetrahydrofuran (12 ml) was added methyl4-[(E)-2-(4-pyridyl)vinyl]benzoate (1.17 g), and after stirring for 2hours at ambient temperature, ammonia solution and methanol were addedthereto. The mixture was stirred for 2 hours at ambient temperature.Insoluble material was filtered off, and the filtrate was washed withwater and brine, dried over magnesium sulfate and concentrated in vacuo.The residue was crystallized with diisopropyl ether to give4-[(E)-2-(4-pyridyl)vinyl]benzyl alcohol (762 mg).

mp: 211-213° C.

NMR (DMSO-d₆, δ): 4.51 (2H, d, J=5 Hz), 5.23 (1H, t, J=5 Hz), 7.22 (1H,d, J=16 Hz), 7.37 (2H, d, J=7.5 Hz), 7.49-7.59 (3H, m), 7.62 (2H, d,J=7.5 Hz), 8.53 (2H, d, J=6 Hz)

(3) To a solution of 4-[(E)-2-(4-pyridyl)vinyl]benzyl alcohol (740 mg)and triethylamine (1.77 g) in dimethyl sulfoxide (3 ml) was added sulfurtrioxide-pyridine complex (1.11 g) at ambient temperature, and afterstirring for 4 hours, water was added thereto. The mixture was extractedwith ethyl acetate, and the extract was washed with water and brine,dried over magnesium sulfate and concentrated in vacuo. The residue waspurified by flash chromatography (chloroform-ethyl acetate) andcrystallized with diisopropyl ether to give4-[(E)-2-(4-pyridyl)vinyl]-benzaldehyde (518 mg).

mp: 116-117° C.

NMR (CDCl₃, δ) 7.16 (1H, d, J=16 Hz), 7.33 (1H, d, J=16 Hz), 7.40 (2H,d, J=6 Hz), 7.69 (2H, d, J=7.5 Hz), 7.90 (2H, d, J=7.5 Hz), 8.62 (2H, d,J=6 Hz)

(4) To a solution of 4-[(E)-2-(4-pyridyl)vinyl]benzaldehyde (50 mg) inpyridine (0.025 ml) and ethanol (0.075 ml) was added malonic acid (27.4mg), and the mixture was refluxed for 7 hours. After cooling, ethylacetate was added thereto, the resulting precipitates were collected byfiltration to give 4-[(E)-2-(4-pyridyl)vinyl]cinnamic acid (28 mg).

mp: >300° C.

NMR (DMSO-d₆, δ): 6.58 (1H, d, J=15 Hz), 7.35 (1H, d, J=16 Hz),7.53-7.64 (4H, m), 7.70 (2H, d, J=7.5 Hz), 7.76 (2H, d, J=7.5 Hz), 8.56(2H, d, J=6 Hz)

Preparation 37

(1) To a solution of methyl 4-[(Z)-2-(4-pyridyl)vinyl]-benzoate (570 mg)in methanol (5.7 ml) was added 10% palladium on carbon, and the mixturewas stirred for 4 hours at ambient temperature under hydrogenatmosphere. Insoluble material was filtered off, and the filtrate wasconcentrated in vacuo. The residue was crystallized with n-hexane togive methyl 4-[2-(4-pyridyl)ethyl]benzoate (539 mg).

mp: 62-64° C.

NMR (CDCl₃, δ) 1.81 (1H, br s), 2.91 (4H, s), 4.68 (2H, br d, J=5 Hz),7.08 (2H, d, J=6 Hz), 7.15 (2H, d, J=7.5 Hz), 7.29 (2H, d, J=7.5 Hz),8.48 (2H, br d, J=6 Hz)

(2) 4-[2-(4-Pyridyl)ethyl]benzyl alcohol was obtained according to asimilar manner to that of Preparation 36-(2).

mp: 163-166° C.

NMR (CDCl₃, δ): 2.96-3.04 (4H, m), 3.90 (3H, s), 7.12 (2H, d, J=6 Hz),7.20 (2H, d, J=7.5 Hz), 7.96 (2H, d, J=7.5 Hz), 8.50 (2H, br d, J=6 Hz)

(3) 4-[2-(4-Pyridyl)ethyl]benzaldehyde was obtained according to asimilar manner to that of Preparation 36-(3).

NMR (CDCl₃, δ): 2.90-3.08 (4H, m), 7.06 (2H, d, J=6 Hz), 7.30 (2H, d,J=7.5 Hz), 7.80 (2H, d, J=7.5 Hz), 8.49 (2H, br d, J=6 Hz)

(4) 4-[2-(4-Pyridyl)ethyl]cinnamic acid was obtained according to asimilar manner to that of Preparation 36-(4).

mp: >300° C.

NMR (DMSO-d₆, δ): 2.91 (4H, br s), 6.47 (1H, d, J=15 Hz), 7.20-7.30 (4H,m), 7.49-7.62 (3H, m), 8.43 (2H, d, J=6 Hz)

Preparation 38

(1) To a solution of 2-amino-5-bromo-3-methylpyridine (300 mg) inN,N-dimethylaniline (486 mg) was added acetyl chloride (138 mg), and themixture was stirred for 3 hours at 70° C. The reaction mixture waspoured into water, and extracted with ethyl acetate. The extract waswashed with water and brine, dried over magnesium sulfate and evaporatedin vacuo. The residue was purified by silica gel column chromatography(chloroform) to give 2-acetamido-5-bromo-3-methylpyridine (120 mg).

NMR (CDCl₃, δ): 2.25 (6H, s-like), 7.50 (1H, br s), 7.70 (1H, d, J=2Hz), 8.29 (1H, d, J=2 Hz)

(2) To a solution of 2-acetamido-5-bromo-3-methylpyridine (110 mg) andtri-n-butylamine (196 mg) in xylene were added palladium(II) acetate (1mg) and triphenylphosphine (1 mg) under nitrogen atmosphere, and themixture was heated at 150° C. Acrylic acid (41.5 mg) was added thereto,and the mixture was stirred for 7 hours at the same temperature. Aftercooling to ambient temperature, ethyl acetate and saturated sodiumbicarbonate solution were added to the reaction mixture, and separatedaqueous layer was adjusted to pH 4 with 4N hydrochloric acid. Themixture was extracted with chloroform. The extract was washed with waterand brine, dried over magnesium sulfate and evaporated in vacuo. Theresidue was collected by filtration and washed with diisopropyl ether togive (E)-3-(6-acetamido-5-methylpyridin-3-yl)acrylic acid (89 mg).

NMR (CDCl₃, δ): 2.03 (3H, s), 2.14 (3H, s), 6.46 (1H, d, J=16 Hz), 7.09(1H, d, J=16 Hz), 7.81 (1H, s-like), 8.30 (1H, s-like)

Preparation 39

The following compounds were obtained according to a similar manner tothat of Example 9.

(1) 3-[2,6-Dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-amino-N-methylaniline (from3-hydroxy-2-amino-N-methylaniline and2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzylchloride)

NMR (DMSO-d₆, δ) 2.24 (3H, s), 2.40 (3H, s), 2.71 (3H, d, J=5.5 Hz),2.79 (3H, d, J=5.5 Hz), 3.10 (3H, s), 3.50 (1H, dd, J=16.5, 5.5 Hz),3.67 (1H, dd, J=16.5, 5.5 Hz), 3.96 (2H, br s), 4.68 (1H, q, J=5.5 Hz),5.03 (2H, s), 6.20 (1H, d, J=7.5 Hz), 6.49-6.59 (2H, m), 6.88 (1H, d,J=16.0 Hz), 7.22 (1H, d, J=8.5 Hz), 7.27 (1H, d, J=8.5 Hz), 7.42 (1H, d,J=16.0 Hz), 7.63 (2H, d, J=8.5 Hz), 7.85 (2H, d, J=8.5 Hz), 8.25 (1H, t,J=4.5 Hz), 8.48 (1H, q, J=4.5 Hz)

(2)3-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-aminoaniline(from 3-hydroxy-2-aminoaniline and3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzylchloride)

NMR (CDCl₃, δ): 2.22 (3H, s), 3.28 (3H, s), 3.50 (4H, br s), 3.69 (1H,dd, J=17, 4 Hz), 3.94 (1H, dd, J=17, 5 Hz), 5.34 (2H, s), 6.40-6.50 (2H,m), 6.60-6.76 (3H, m), 7.32 (1H, d, J=7.5 Hz), 7.50 (1H, d, J=7.5 Hz),7.53 (1H, d, J=15 Hz), 7.85 (1H, dd, J=7.5, 2 Hz), 7.27-7.36 (4H, m),7.49 (1H, d, J=7.5 Hz), 7.51 (1H, d, J=15 Hz), 7.84 (1H, br d, J=7.5Hz), 8.09 (1H, br s), 8.22 (1H, br d, J=7.5 Hz), 8.36 (1H, br s)

(3)2-Amino-3-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)-acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-N-ethylaniline(from 3-hydroxy-2-amino-N-ethylaniline and3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6dichlorobenzylchloride)

(This compound was used as a starting compound of Example 18-(2) withoutpurification.)

(4) 3-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-amino-N-methylaniline(from 3-hydroxy-2-amino-N-methylaniline and3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzylbromide)

(This compound was used as a starting compound of Example 18-(3) withoutpurification.)

Preparation 40

(1)3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichlorobenzenewas obtained from3-(N-glycyl-N-methylamino)-1-(tert-butyldiphenylsilyloxymethyl)-2,6-dichlorobenzeneand (E)-3-(6-acetamidopyridin-3-yl)acrylic acid according to a similarmanner to that of Preparation 16-(2).

mp: 194-196° C.

NMR (CDCl₃, δ): 1.06 (9H, s), 2.22 (3H, s), 3.23 (3H, s), 3.57 (1H, dd,J=17, 4 Hz), 3.94 (1H, dd, J=17, 5 Hz), 4.92 (1H, d, J=10 Hz), 4.98 (1H,d, J=10 Hz), 6.44 (1H, d, J=15 Hz), 6.63 (1H, br s), 7.22 (1H, d, J=8Hz), 7.35-7.48 (6H, m), 7.52 (1H, d, J=15 Hz), 7.70-7.77 (4H, m), 7.83(1H, dd, J=8, 3 Hz), 8.05 (1H, br s), 8.22 (1H, d, J=8 Hz), 8.36 (1H, d,J=3 Hz)

(2)3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-1-hydroxymethyl-2,6-dichlorobenzenewas obtained according to a similar manner to that of Preparation16-(3).

mp: 207-209° C.

NMR (DMSO-d₆, δ): 2.10 (3H, s), 3.10 (3H, s), 3.47 (1H, dd, J=17, 4 Hz),3.76 (1H, dd, J=17, 5 Hz), 4.74 (1H, d, J=5 Hz), 5.35 (1H, br s), 6.79(1H, d, J=15 Hz), 7.37 (1H, d, J=15 Hz), 7.61 (1H, d, J=8 Hz), 7.65 (1H,d, J=8 Hz), 7.98 (1H, dd, J=8, 3 Hz), 8.11 (1H, d, J=8 Hz), 8.21 (1H, t,J=5 Hz), 8.47 (1H, s)

(3)3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzylbromide was obtained according to a similar manner to that ofPreparation 16-(4).

mp: 222-223° C.

NMR (CDCl₃ --CD₃ OD, δ): 2.22 (3H, s), 3.27 (3H, s), 3.60 (1H, dd, J=17,3 Hz), 3.94 (1H, dd, J=17, 3 Hz), 4.78 (2H, s), 6.49 (1H, d, J=15 Hz),7.31 (1H, d, J=8 Hz), 7.49 (1H, d, J=8 Hz), 7.51 (1H, d, J=15 Hz), 7.88(1H, dd, J=8, 3 Hz), 8.23 (1H, br d, J=8 Hz), 8.33 (1H, d, J=3 Hz)

Preparation 41

4-Acetamido-3-methylcinnamic acid was obtained from4-acetamido-3-methylbenzaldehyde and malonic acid according to a similarmanner to that of Preparation 36-(4).

mp: 262-263° C. (dec.)

NMR (DMSO-d₆, δ): 2.09 (3H, s), 2.23 (3H, s), 6.43 (1H, d, J=16 Hz),7.43-7.61 (4H), 9.33 (1H, s)

Preparation 42

5-Hydroxymethyl-2-[(E)-2-(4-pyridyl)vinyl]pyridine was obtained frommethyl 2-[(E)-2-(4-pyridyl)vinyl]pyridin-5-carboxylate according to asimilar manner to that of Preparation 36-(2).

mp: >198.9° C.

NMR (CDCl₃, δ): 4.73 (2H, s), 7.34 (1H, d, J=16 Hz), 7.40-7.49 (3H, m),7.53 (1H, d, J=16 Hz), 8.53-8.65 (3H, m)

Preparation 43

(1) To a solution of methyl 3,4-dihydro-2(1H)-quinolinone-6-carboxylate(500 mg) in tetrahydrofuran was dropwise added 2M solution ofborane-methyl sulfide complex in tetrahydrofuran (2.5 ml) underice-cooling, and the mixture was refluxed for 45 minutes. After cooling,methanol (1 ml) was dropwise added thereto, and the mixture was stirredfor 1 hour. The solvent was removed, and ethyl acetate and water wereadded to the residue. The organic layer was washed with water, saturatedsodium bicarbonate solution and brine, dried over magnesium sulfate andconcentrated in vacuo. The residue was pulverized with diisopropylether-n-hexane to give methyl 1,2,3,4-tetrahydroquinoline-6-carboxylateas solid.

mp: 75-84° C.

NMR (CDCl₃, δ): 2.93 (2H, quint, J=7 Hz), 2.76 (2H, t, J=7 Hz), 3.33(2H, t, J=7 Hz), 3.83 (3H, s), 4.29 (1H, br s), 6.39 (1H, d, J=8 Hz),7.59-7.68 (2H, m)

(2) 6-Hydroxymethyl-1,2,3,4-tetrahydroquinoline was obtained accordingto a similar manner to that of Preparation 36-(2).

NMR (CDCl₃, δ): 1.53 (1H, t, J=6 Hz), 1.90 (2H, quint, J=7 Hz), 2.73(2H, t, J=7 Hz), 3.28 (2H, t, J=7 Hz), 4.49 (2H, d, J=6 Hz), 6.44 (1H,d, J=8 Hz), 6.90-7.00 (2H, m)

(3) To a solution of 6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (314mg) in methanol (4 ml) was dropwise added acetic anhydride (589 mg)under ice-cooling, and the mixture was stirred for 1 hour at the sametemperature. The solvent was removed in vacuo, and ethyl acetate andsaturated sodium bicarbonate solution were added to the residue. Theorganic layer was washed with water and brine, dried and concentrated invacuo. The residue was purified by preparative thin-layer chromatography(n-hexane:ethyl acetate =1:2, v/v) to give1-acetyl-6-hydroxymethyl-1,2,3,4-tetrahydroquinoline (227 mg).

mp: 95-106° C.

NMR (CDCl₃, δ): 1.70 (1H, t-like), 1.96 (2H, quint, J=7 Hz), 2.24 (3H,s), 2.75 (2H, t, J=7 Hz), 3.80 (2H, t, J=7 Hz), 4.67 (2H, d, J=6 Hz),6.96-7.36 (3H, m)

Preparation 44

(1) A mixture of 3-methoxy-4-nitrobenzyl alcohol (1.0 g) and 10%palladium on carbon (100 mg) in methanol was stirred for 2 hours under 3atmospheric pressure of hydrogen. After filtration, the filtrate wasconcentrated in vacuo to give 4-amino-3-methoxybenzyl alcohol (910 mg)as an oil.

NMR (CDCl₃, δ): 3.77 (2H, br s), 3.84 (3H, s), 4.56 (2H, s), 6.66 (1H,d, J=8 Hz), 6.76 (1H, d, J=8 Hz), 6.81 (1H, s)

(2) To a solution of 4-amino-3-methoxybenzyl alcohol (900 mg) inmethanol was added acetic anhydride (1.8 g) under ice cooling, and themixture was stirred for 1 hour at the same temperature. Afterevaporation, the residue was dissolved in ethyl acetate, and thesolution was washed with sodium bicarbonate solution, water and brine,dried over magnesium sulfate and concentrated in vacuo to give4-acetamido-3-methoxybenzyl alcohol (840 mg) as solid.

mp: 104° C.

NMR (CDCl₃, δ): 1.69 (1H, t, J=5 Hz), 2.20 (3H, s), 3.90 (3H, s), 4.65(2H, d, J=5 Hz), 6.88-6.97 (2H, n), 7.74 (1H, br s), 8.32 (1H, d, J=8Hz)

Preparation 45

The following compounds were obtained according to a similar manner tothat of Preparation 36-(3).

(1) 1-Acetyl-6-formyl-1,2,3,4-tetrahydroquinoline

NMR (CDCl₃, δ): 2.01 (2H, quint, J=7 Hz), 2.29 (3H, s), 2.82 (2H, t, J=7Hz), 3.81 (2H, t, J=7 Hz), 7.46-7.60 (1H, br peak), 7.65-7.74 (2H, m),9.93 (1H, s)

(2) 4-Acetamido-3-methoxybenzaldehyde

mp: 145° C.

NMR (CDCl₃, δ): 2.25 (3H, s), 3.97 (3H, s), 7.41 (1H, d, J=2 Hz), 7.48(1H, dd, J=2, 8 Hz), 7.99 (1H, br s), 8.59 (1H, d, J=8 Hz), 9.88 (1H, s)

(3) 5-Formyl-2-[(E)-2-(4-pyridyl)vinyl]pyridine

mp: 131-136° C.

NMR (CDCl₃, δ): 7.40 (1H, d, J=16 Hz), 7.47 (2H, d, J=6 Hz), 7.56 (1H,d, J=8 Hz), 7.78 (1H, d, J=16 Hz), 8.19 (1H, dd, J=2, 8 Hz), 8.65 (2H,d, J=6 Hz), 9.07 (1H, d, J=2 Hz), 10.12 (1H, s)

Preparation 46

The following compounds were obtained according to a similar manner tothat of Preparation 36-(4).

(1) (E)-3-(1-Acetyl-1,2,3,4-tetrahydroquinolin-6-yl)acrylic acid

NMR (DMSO-d₆, δ): 1.85 (2H, quint, J=7 Hz), 2.17 (3H, s), 2.73 (2H, t,J=7 Hz), 3.68 (2H, t, J=7 Hz), 6.46 (1H, d, J=16 Hz), 7.41-7.63 (4H, m)

(2) 4-Acetamido-3-methoxycinnamic acid

mp: 221.5-230° C.

NMR (DMSO-d₆, δ): 2.10 (3H, s), 3.89 (3H, s), 6.52 (1H, d, J=16 Hz),7.20 (1H, d, J=8 Hz), 7.38 (1H, s-like), 7.53 (1H, d, J=16 Hz), 8.07(1H, d, J=8 Hz), 9.26 (1H, s)

(3) (E)-3-[6-[(E)-2-(4-Pyridyl)vinyl]pyridin-3-yl]acrylic acid

mp: >250° C.

NMR (DMSO-d₆, δ): 6.71 (1H, d, J=16 Hz), 7.56-7.77 (6H, m), 8.20 (1H,dd, J=2, 8 Hz), 8.59 (2H, d, J=6 Hz), 8.88 (1H, d, J=2 Hz)

Preparation 47

(1) 4-Formyl-2-methoxybenzoic acid was obtained from4-hydroxymethyl-2-methoxybenzoic acid according to a similar manner tothat of Preparation 36-(3).

NMR (CDCl₃, δ): 4.04 (3H, s), 7.47-7.55 (2H, m), 8.04 (1H, d, J=8 Hz),10.21 (1H, s)

(2) To a solution of 4-formyl-2-methoxybenzoic acid in tetrahydrofuranwas added methyl (triphenylphosphranilidene)acetate at ambienttemperature, and the mixture was stirred for 1 hour and thenconcentrated in vacuo. Ethyl acetate and saturated sodium bicarbonatesolution were added to the residue, and separated aqueous layer wasadjusted to pH 4 with 4N hydrochloric acid. The mixture was extractedwith ethyl acetate. The extract was washed with water and brine, driedover magnesium sulfate and evaporated in vacuo. The residue was washedwith hot diisopropyl ether to give methyl 4-carboxy-3-methoxycinnamate.

NMR (CDCl₃, δ): 3.84 (3H, s), 4.13 (3H, s), 6.54 (1H, d, J=16 Hz), 7.14(1H, s), 7.31 (1H, d, J=8 Hz), 7.67 (1H, d, J=16 Hz), 8.21 (1H, d, J=8Hz)

(3) Methyl 3-methoxy-4-methylcarbamoylcinnamate was obtained from methyl4-carboxy-3-methoxycinnamate and methylamine hydrochloride according toa similar manner to that of Example 26.

NMR (CDCl₃, δ): 3.01 (3H, d, J=5 Hz), 3.82 (3H, s), 4.00 (3H, s), 6.48(1H, d, J=16 Hz), 7.07 (1H, s), 7.25 (1H, d, J=8 Hz), 7.67 (1H, d, J=16Hz), 7.78 (1H, br s), 8.24 (1H, d, J=8 Hz)

(4) To a solution of methyl 3-methoxy-4-methylcarbamoyl-cinnamate (300mg) in methanol was added 1N sodium hydroxide solution (1.5 ml) atambient temperature, and the mixture was stirred at 50° C. for 5 hours.The solvent was distilled off, and the residue was dissolved in water.The solution was washed with diethyl ether, and adjusted to pH 4 with 1Nhydrochloric acid. The resulting precipitates were collected byfiltration and washed with water to give3-methoxy-4-methylcarbamoylcinnamic acid (250 mg).

NMR (DMSO-d₆, δ): 2.78 (3H, d, J=5 Hz), 3.91 (3H, s), 6.66 (1H, d, J=16Hz), 7.31 (1H, d, J=8 Hz), 7.43 (1H, s), 7.59 (1H, d, J=16 Hz), 7.73(1H, d, J=8 Hz), 8.16 (1H, q-like)

Preparation 48

9-Hydroxy-3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazole was obtainedfrom 9-benzyloxy-3,4-dihydro-2H-[1,3]oxazino[3,2-a]benzimidazoleaccording to a similar manner to that of Preparation 35.

mp: 227-230° C.

NMR (CDCl₃, δ): 2.28-2.39 (2H, m), 4.10 (2H, br t, J=7.5 Hz), 4.54 (2H,br t, J=6 Hz), 6.71 (1H, d, J=7.5 Hz), 6.80 (1H, d, J=7.5 Hz), 7.06 (1H,t, J=7.5 Hz)

Example 16

(1)2-Amino-3-[2,6-dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]benzyloxy]-N-methylanilinewas obtained from 2-amino-3-hydroxy-N-methylaniline and2,6-dichloro-1-methylsulfonyloxymethyl-3-[N-methyl-N-(phthalimidoacetyl)-amino]benzeneaccording to a similar manner to that of Example 1.

NMR (CDCl₃, δ) 2.83 (3H, s), 3.25 (3H, s), 4.09 (2H, s), 5.33 (1H, d,J=10 Hz), 5.41 (1H, d, J=10 Hz), 6.41 (1H, d, J=8 Hz), 6.65 (1H, d, J=8Hz), 6.85 (1H, t, J=8 Hz), 7.44-7.56 (2H, m), 7.68-7.78 (2H, m),7.80-7.90 (2H, m)

(2)4-[2,6-Dichloro-3-[N-(phthalimidoacetyl)-N-methylamino]-benzyloxy]-2-methoxy-1-methyl-1H-benzimidazolewas obtained according to a similar manner to that of Preparation15-(2).

NMR (CDCl₃, δ) 3.24 (3H, s), 3.53 (3H, s), 4.10 (2H, s), 4.20 (3H, s),5.63-5.74 (2H, m), 6.80-6.88 (2H, m), 7.10 (1H, t, J=8 Hz), 7.43-7.55(2H, m), 7.67-7.76 (2H, m), 7.80-7.90 (2H, m)

(3)4-[3-(N-Glycyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazolewas obtained according to a similar manner to that of Example 3.

NMR (CDCl₃, δ): 3.00 (1H, d, J=15 Hz), 3.10 (1H, d, J=15 Hz), 3.21 (3H,s), 3.51 (3H, s), 4.16 (3H, s), 5.62 (2H, s), 6.78-6.88 (2H, m), 7.09(1H, t, J=8 Hz), 7.23 (1H, d, J=8 Hz), 7.43 (1H, d, J=8 Hz)

Example 17

The following compounds were obtained according to a similar manner tothat of Example 7.

(1)4-[3-[N-(4-Acetamido-3-methylcinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ) 2.22 (3H, s), 2.27 (3H, s), 3.25 (3H, s), 3.55 (3H, s),3.65 (1H, dd, J=4, 18 Hz), 3.94 (1H, dd, J=4, 18 Hz), 4.19 (3H, s), 5.65(2H, s), 6.41 (1H, d, J=16 Hz), 6.60 (1H, br peak), 6.80-6.89 (2H, m),7.00 (1H, br s), 7.12 (1H, t, J=8 Hz), 7.23-7.41 (3H, m), 7.41-7.55 (2H,m), 7.94 (1H, d, J=8 Hz)

(2) 4-[3-[N-[3-Methoxy-4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 3.02 (3H, d, J=5 Hz), 3.27 (3H, s), 3.55 (3H, s), 3.67(1H, dd, J=4, 18 Hz), 3.93 (1H, dd, J=4, 18 Hz), 3.97 (3H, s), 4.19 (3H,s), 5.65 (2H, s), 6.53 (1H, d, J=16 Hz), 6.69 (1H, t-like), 6.81-6.89(2H, m), 7.03 (1H, s-like), 7.11 (1H, t, J=8 Hz), 7.23 (1H, d, J=8 Hz),7.30 (1H, d, J=8 Hz), 7.47 (1H, d, J=8 Hz), 7.55 (1H, d, J=16 Hz), 7.79(1H, q-like), 8.21 (1H, d, J=8 Hz)

(3)4-[2,6-Dichloro-3-[N-methyl-N-[4-(2-oxopyrrolidin-1-yl)-cinnamoylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ) 2.11-2.22 (2H, m), 2.62 (2H, t, J=7.5 Hz), 3.27 (3H, s),3.53 (3H, s), 3.66 (1H, dd, J=17, 4 Hz), 3.88 (2H, t, J=7.5 Hz), 3.94(1H, d, J=14, 5 Hz), 4.19 (3H, s), 5.65 (2H, s), 6.42 (1H, d, J=15 Hz),6.60 (1H, br t, J=5 Hz), 6.81-6.88 (2H, m), 7.10 (1H, t, J=7.5 Hz), 7.30(1H, d, J=7.5 Hz), 7.45-7.58 (4H, m), 7.66 (2H, d, J=7.5 Hz)

(4)4-[2,6-Dichloro-3-[N-[4-[N-methoxyacetyl-N-(3-pyridylmethyl)amino]cinnamoylglycyl]-N-methylamino]-benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 3.28 (3H, s), 3.34 (3H, s), 3.53 (3H, s), 3.68 (1H, dd,J=17, 4 Hz), 3.80 (2H, s), 3.95 (1H, d, J=14, 5 Hz), 4.19 (3H, s), 4.89(2H, s), 5.65 (2H, s), 6.46 (1H, d, J=15 Hz), 6.68 (1H, br s), 6.81-6.89(2H, m), 6.99 (2H, d, J=7.5 Hz), 7.11 (1H, t, J=7.5 Hz), 7.20-7.33 (2H,m), 7.45-7.59 (4H, m), 7.67 (1H, br d, J=7.5 Hz), 8.37 (1H, br s), 8.51(1H, d, J=5 Hz)

(5)4-[2,6-Dichloro-3-[N-methyl-N-[4-[(E)-2-(4-pyridyl)-vinyl]cinnamoylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 3.28 (3H, s), 3.52 (3H, s), 3.68 (1H, dd, J=17, 4 Hz),3.95 (1H, d, J=14, 5 Hz), 4.19 (3H, s), 5.66 (2H, s), 6.50 (1H, d, J=15Hz), 6.64 (1H, br s), 6.80-6.88 (2H, m), 7.05 (1H, d, J=15 Hz), 7.11(1H, t, J=7.5 Hz), 7.30 (1H, d, J=7.5 Hz), 7.37 (2H, d, J=7.5 Hz),7.45-7.61 (7H, m), 8.59 (1H, d, J=7.5 Hz)

(6) 4-[2,6-Dichloro-3-[N-methyl-N-[4-[2-(4-pyridyl)ethyl]-cinnamoylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazol

NMR (CDCl₃, δ): 2.91 (4H, br s), 3.27 (3H, s), 3.52 (3H, s), 3.65 (1H,dd, J=17, 4 Hz), 3.94 (1H, d, J=14, 5 Hz), 4.19 (3H, s), 5.64 (2H, s),6.43 (1H, d, J=15 Hz), 6.61 (1H, br s), 6.81-6.88 (2H, m), 7.02-7.18(5H, m), 7.30 (1H, d, J=7.5 Hz), 7.42 (2H, br d, J=7.5 Hz), 7.48 (1H, d,J=7.5 Hz), 7.54 (1H, d, J=15 Hz), 8.48 (1H, d, J=7.5 Hz)

(7)4-[2,6-Dichloro-3-[N-methyl-N-[(E)-3-[6-[(E)-2-(4-pyridyl)vinyl]pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 3.28 (3H, s), 3.52 (3H, s), 3.68 (1H, dd, J=17, 4 Hz),3.96 (1H, d, J=14, 5 Hz), 4.19 (3H, s), 5.67 (2H, s), 6.58 (1H, d, J=15Hz), 6.69 (1H, br s), 6.81-6.88 (2H, m), 7.11 (1H, t, J=7.5 Hz), 7.30(1H, d, J=15 Hz), 7.34 (1H, d, J=15 Hz), 7.39-7.51 (4H, m), 7.58 (1H, d,J=8 Hz), 7.62 (1H, d, J=8 Hz), 7.82 (1H, br d, J=7.5 Hz), 8.61 (2H, brd, J=7.5 Hz), 8.74 (1H, br s)

(8) 4-[3-[N-[(E)-3-(1-Acetyl-1,2,3,4-tetrahydroquinolin-6-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 1.96 (2H, m), 2.23 (3H, s), 2.73 (2H, t, J=7 Hz), 3.25(3H, s), 3.52 (3H, s), 3.64 (1H, dd, J=4, 16 Hz), 3.78 (2H, t, J=7 Hz),3.93 (1H, dd, J=4, 16 Hz), 4.19 (3H, s), 5.15 (2H, s), 6.42 (1H, d, J=16Hz), 6.69 (1H, br peak), 6.80-6.88 (2H, m), 7.10 (1H, t, J=8 Hz),7.20-7.38 (4H, m), 7.43-7.58 (2H, m)

(9)4-[3-[N-[(E)-3-(6-Acetamido-5-methylpyridin-3-yl)-acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ) 2.23 (3H, s), 2.31 (3H, s), 3.27 (3H, s), 3.51 (3H, s),3.66 (1H, dd, J=4, 18 Hz), 3.95 (1H, dd, J=4, 18 Hz), 4.17 (3H, s), 5.64(2H, s), 6.48 (1H, d, J=16 Hz), 6.79 (1H, br peak), 6.81-6.89 (2H, m),7.10 (1H, t, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.43-7.56 (2H, m), 7.65 (1H,s-like), 7.83 (1H, br s), 8.31 (1H, s-like)

(10)4-[2,6-Dichloro-3-[N-[(E)-3-(6-ethoxycarbonylpyridin-3-yl)acryloylglycyl]-N-methylamino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 1.46 (3H, t, J=7.5 Hz), 3.27 (3H, s), 3.52 (3H, s), 3.70(1H, dd, J=4, 18 Hz), 3.90 (1H, dd, J=4, 18 Hz), 4.17 (3H, s), 4.49 (2H,q, J=7.5 Hz), 5.65 (2H, s), 6.65 (1H, d, J=16 Hz), 6.75 (1H, t-like),6.81-6.89 (2H, m), 7.11 (1H, t, J=8 Hz), 7.31 (1H, d, J=8 Hz), 7.48 (1H,d, J=8 Hz), 7.61 (1H, d, J=16 Hz), 7.93 (1H, d, J=8 Hz), 8.13 (1H, d,J=8 Hz), 8.35 (1H, s-like)

(11)4-[3-[N-[(E)-3-(6-Aminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 3.27 (3H, s), 3.54 (3H, s), 3.65 (1H, dd, J=17, 4 Hz),3.94 (1H, d, J=14, 5 Hz), 4.19 (3H, s), 4.69 (2H, s), 5.64 (2H, s), 6.30(1H, d, J=15 Hz), 6.50 (1H, d, J=7.5 Hz), 6.56 (1H, br s), 6.81-6.88(2H, m), 7.10 (1H, t, J=7.5 Hz), 7.30 (1H, d, J=7.5 Hz), 7.42-7.50 (2H,m), 7.61 (1H, br d, J=7.5 Hz), 8.18 (1H, br s)

(12)4-[3-[N-(4-Acetamido-3-methoxycinnamoylglycyl)-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 2.20 (3H, s), 3.28 (3H, s), 3.53 (3H, s), 3.66 (1H, dd,J=17, 4 Hz), 3.89-4.00 (4H, m), 4.19 (3H, s), 5.65 (2H, s), 6.40 (1H, d,J=15 Hz), 6.60 (1H, br s), 6.81-6.89 (2H, m), 7.00 (1H, br s), 7.08-7.16(2H, m), 7.30 (1H, d, J=7.5 Hz), 7.48 (1H, d, J=7.5 Hz), 7.50 (1H, d,J=15 Hz), 7.81 (1H, br s), 7.38 (1H, br d, J=7.5 Hz)

(13)4-[2,6-Dichloro-3-[N-[4-(dimethylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 2.98 (3H, br s), 3.11 (3H, br s), 3.27 (3H, s), 3.53(3H, s), 3.65 (1H, dd, J=4, 18 Hz), 3.93 (1H, dd, J=4, 18 Hz), 4.18 (3H,s), 5.63 (2H, s), 6.50 (1H, d, J=16 Hz), 6.55 (1H, t-like), 6.80-6.87(2H, m), 7.10 (1H, t, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.38-7.61 (6H, m)

Example 18

The following compounds were obtained according to a similar manner tothat of Preparation 15-(2).

(1)4-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1H-benzimidazole

NMR (CDCl₃, δ): 2.21 (3H, s), 3.29 (3H, s), 3.59 (1H, br d, J=17 Hz),4.10-4.22 (4H, m), 5.30 (1H, d, J=10 Hz), 5.59 (1H, d, J=10 Hz), 6.48(1H, d, J=15 Hz), 6.78 (1H, br s), 7.83 (1H, d, J=7.5 Hz), 7.12 (1H, t,J=15 Hz), 7.20-7.29 (1H, m), 7.32 (1H, d, J=7.5 Hz), 7.49 (1H, d, J=7.5Hz), 7.65 (1H, d, J=15 Hz), 7.85 (1H, br d, J=7.5 Hz), 8.09 (1H, br s),8.23 (1H, br d, J=7.5 Hz), 8.37 (1H, br s)

(2)4-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-1-ethyl-2-methoxy-1H-benzimidazole

NMR (CDCl₃, δ): 1.35 (3H, t, J=7.5 Hz), 2.22 (3H, s), 3.67 (1H, dd, J=4,18 Hz), 3.94 (1H, dd, J=4, 18 Hz), 4.00 (2H, q, J=7.5 Hz), 4.18 (3H, s),5.64 (2H, s), 6.46 (1H, d, J=16 Hz), 6.69 (1H, t-like), 6.80-6.90 (2H,m), 7.11 (1H, t, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.44-7.58 (2H, m), 7.84(1H, dd, J=2, 8 Hz), 8.08 (1H, s), 8.20 (1H, d, J=8 Hz), 8.35 (2H, d)

(3)4-(3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ) 2.21 (3H, s), 3.28 (3H, s), 3.53 (3H, s), 3.66 (1H, dd,J=17, 4 Hz), 3.95 (1H, dd, J=17, 6 Hz), 4.19 (3H, s), 5.66 (2H, s), 6.46(1H, d, J=15 Hz), 6.68 (1H, t-like), 6.80-6.88 (2H), 7.10 (1H, t, J=8Hz), 7.29 (1H, d, J=8 Hz), 7.44-7.56 (2H), 7.83 (1H, dd, J=8, 2 Hz),8.07 (1H, br s), 8.20 (1H, d, J=8 Hz), 8.35 (1H, br s)

(4)4-[2,6-Dimethyl-3-[N-methyl-N-[4-(methylcarbamoyl)cinnamoylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole

NMR (CDCl₃, δ): 2.35 (3H, s), 2.51 (3H, s), 3.03 (3H, d, J=5 Hz), 3.25(3H, s), 3.55 (3H, s), 3.64 (1H, dd, J=4, 16 Hz), 3.88 (1H, dd, J=4, 16Hz), 4.19 (3H, s), 5.41 (2H, s), 6.15 (1H, br s), 6.53 (1H, d, J=16 Hz),6.72 (1H, br peak), 6.81-6.89 (2H, m), 7.02-7.18 (3H, m), 7.50-7.62 (3H,m), 7.75 (2H, d, J=8 Hz)

Example 19

To a solution of 3-hydroxy-2-amino-N-(2-methoxyethyl)aniline (271 mg) inN,N-dimethylformamide (3 ml) was added sodium hydride (35.7 mg) at 0° C.under nitrogen atmosphere, and after stirring for 30 minutes at the sametemperature, a solution of3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzylchloride (699 mg) in N,N-dimethylformamide (5 ml) was dropwise addedthereto. The mixture was stirred for 1 hour, and water was added to thereaction mixture. The mixture was extracted with chloroform, and theextract was washed with brine, dried over magnesium sulfate andevaporated in vacuo to give a residue containing3-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-amino-N-(2-methoxyethyl)aniline.

To a solution of the obtained residue in acetic acid (2 ml) was addedtetramethyl orthocarbonate (304 mg) at ambient temperature, and themixture was allowed to stand for 20 hours. The reaction mixture wasconcentrated, and the residue was purified by silica gel columnchromatography (chloroform:methanol=50:1, v/v) to give4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-(2-methoxyethyl)-1H-benzimidazole(96 mg).

NMR (CDCl₃, δ): 2.23 (3H, s), 3.27 (3H, s), 3.32 (3H, s), 3.62-3.73 (2H,m), 3.95 (1H, dd, J=4, 18 Hz), 4.13 (2H, t, J=7 Hz), 4.20 (3H, s), 5.65(2H, s), 6.46 (1H, d, J=16 Hz), 6.67 (1H, t-like), 6.83 (1H, d, J=8 Hz),6.92 (1H, d, J=8 Hz), 7.10 (1H, t, J=8 Hz), 7.30 (1H, d, J=8 Hz),7.45-7.58 (2H, m), 7.85 (1H, dd, J=8, 2 Hz), 8.06 (1H, s), 8.21 (1H, d,J=8 Hz), 8.35 (1H, d, J=2 Hz)

Example 20

A mixture of3-[2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-amino-N-methylaniline(65.3 mg), 1,1'-thiocarbonyldiimidazole (33.0 mg) and anhydroustetrahydrofuran (0.7 ml) was stirred for 7 hours at ambient temperature.The reaction mixture was diluted with chloroform and washed with waterand brine. The organic layer was dried over magnesium sulfate andevaporated in vacuo. The residue was washed with diethyl ether to give4-[2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-mercapto-1-methyl-1H-benzimidazole(51.8 mg) as pale brown solid.

mp: 278.5-292° C.

NMR (DMSO-d₆, δ): 2.26 (3H, s), 2.42 (3H, s), 2.79 (3H, d, J=4.5 Hz),3.11 (3H, s), 3.49 (1H, dd, J=16.5, 4.5 Hz), 3.63 (3H, s), 3.71 (1H, dd,J=16.5, 4.5 Hz), 5.23 (1H, d, J=11.0 Hz), 5.30 (1H, d, J=11.0 Hz), 6.90(1H, d, J=16.0 Hz), 7.03 (1H, d, J=8.5 Hz), 7.09 (1H, d, J=8.5 Hz) 7.20(1H, t, J=8.5 Hz), 7.25 (1H, d, J=8.5 Hz), 7.31 (1H, d, J=8.5 Hz), 7.44(1H, d, J=16.0 Hz), 7.64 (2H, d, J=8.5 Hz), 7.85 (2H, d, J=8.5 Hz), 8.27(1H, t, J=4.5 Hz), 8.48 (1H, q, J=4.5 Hz)

Example 21

To a mixture of4-[2,6-dimethyl-3-[N-(4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-2-mercapto-1-methyl-1H-benzimidazole(34.9 mg), potassium carbonate (10.1 mg) and N,N-dimethylformamide (0.4ml) was added methyl iodide (4 μl) at ambient temperature, and themixture was stirred for 16 hours. The reaction mixture was poured intowater, and extracted with chloroform. The extract was washed with waterand brine, dried over magnesium sulfate and evaporated in vacuo. Theresidue was purified by preparative thin layer chromatography (ethylacetate:methanol=10:1, v/v) to give4-[2,6-dimethyl-3-[N-[4-(methylcarbamoyl)cinnamoylglycyl]-N-methylamino]benzyloxy]-1-methyl-2-methylthio-1H-benzimidazole(21.2 mg).

mp: 224.0-225.0° C.

NMR (DMSO-d₆, δ): 2.30 (3H, s), 2.43 (3H, s), 2.67 (3H, s), 2.77 (3H, d,J=5.5 Hz), 3.09 (3H, s), 3.48 (1H, dd, J=16.5, 5.5 Hz), 3.63 (3H, s),3.64 (1H, dd, J=16.5, 5.5 Hz), 5.35 (2H, s), 6.87 (1H, d, J=16.0 Hz),6.90 (1H, m), 7.07-7.15 (2H, m), 7.23 (1H, d, J=8.5 Hz), 7.30 (1H, d,J=8.5 Hz), 7.40 (1H, d, J=16.0 Hz), 7.61 (2H, d, J=8.5 Hz), 7.83 (2H, d,J=8.5 Hz), 8.23 (1H, t, J=5.5 Hz), 8.47 (1H, q, J=5.5 Hz)

Example 22

To a solution of4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1H-benzimidazole(100 mg) and 2-dimethylaminoethyl chloride hydrochloride (25.6 mg) inN,N-dimethylformamide (2 ml) was added potassium carbonate (92.5 mg) atambient temperature, and the mixture was stirred for 28 hours at thesame temperature. The reaction mixture was poured into water, andextracted with chloroform. The extract was washed with water and brine,dried over magnesium sulfate and evaporated in vacuo. The residue waspurified by preparative thin layer chromatography to give4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-(2-dimethylaminoethyl)-1H-benzimidazole(11 mg) and7-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-(2-dimethylaminoethyl)-1H-benzimidazole(38 mg).

4-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-(2-dimethylaminoethyl)-1H-benzimidazole

NMR (CDCl₃, δ): 2.22 (3H, s), 2.31 (6H, s), 2.63 (2H, t, J=7.5 Hz), 3.26(3H, s), 3.67 (1H, dd, J=4, 18 Hz), 3.96 (1H, dd, J=4, 18 Hz), 4.06 (2H,t, J=7.5 Hz), 4.19 (3H, s), 5.65 (2H, s), 6.45 (1H, d, J=16 Hz),6.70-6.79 (1H, m), 6.79-6.92 (2H, m), 7.10 (1H, t, J=8 Hz), 7.31 (1H, d,J=8 Hz), 7.43-7.58 (2H, m), 7.83 (1H, dd, J=2, 8 Hz), 8.22 (1H, d, J=8Hz), 8.26-8.39 (2H, m)

7-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-(2-dimethylaminoethyl)-1H-benzimidazole

NMR (CDCl₃, δ): 2.01 (6H, s), 2.22 (3H, s), 2.51 (2H, t, J=8 Hz), 3.28(3H, s), 3.65 (1H, dd, J=4, 18 Hz), 3.95 (1H, dd, J=4, 18 Hz), 4.06-4.18(5H, m), 5.45 (2H, s), 6.45 (1H, d, J=16 Hz), 6.62 (1H, t-like), 6.83(1H, d, J=8 Hz), 7.11 (1H, t, J=8 Hz), 7.20-7.30 (1H, m), 7.36 (1H, d,J=8 Hz), 7.47-7.56 (2H, m), 7.85 (1H, d, J=8 Hz), 8.00 (1H, s), 8.21(1H, d, J=8 Hz), 8.35 (1H, d, J=2 Hz)

Example 23

(1)4-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-1-[2-(tert-butyldiphenylsilyloxy)ethyl]-2-methoxy-1H-benzimidazoleand7-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-1-[2-(tert-butyldiphenylsilyloxy)ethyl]-2-methoxy-1H-benzimidazolewere obtained from4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1H-benzimidazoleand 1-(tert-butyldiphenylsilyloxy)-2-methoxyethane according to asimilar manner to that of Example 22.

4-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-1-[2-(tert-butyldiphenylsilyloxy)ethyl]-2-methoxy-1H-benzimidazole

NMR (CDCl₃, δ): 0.95 (9H, s), 2.21 (3H, s), 3.27 (3H, s), 3.67 (1H, dd,J=17, 4 Hz), 3.84-4.00 (3H, m), 4.06-4.12 (5H, m), 5.66 (2H, s), 6.45(1H, d, J=15 Hz), 6.67 (1H, br s), 6.73 (1H, d, J=7.5 Hz), 6.80 (1H, d,J=7.5 Hz), 7.02 (1H, t, J=7.5 Hz), 7.28-7.57 (13H, m), 7.83 (1H, br dd,J=7.5, 2 Hz), 8.02 (1H, br s), 8.20 (1H, br d, J=7.5 Hz), 8.35 (1H, brs)

7-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-1-[2-(tert-butyldiphenylsilyloxy)ethyl]-2-methoxy-1H-benzimidazole

NMR (CDCl₃, δ): 0.89 (9H, s), 2.22 (3H, s), 3.09 (3H, s), 3.48 (1H, brdd, J=17, 4 Hz), 3.79 (2H, br t, J=5 Hz), 3.87 (1H, br dd, J=17, 5 Hz),4.12 (3H, s), 4.20 (2H, br t, J=5 Hz), 5.29 (2H, s), 6.41 (1H, d, J=15Hz), 6.49 (1H, br s), 6.80 (1H, d, J=7.5 Hz), 7.10-7.44 (14H, m), 7.50(1H, d, J=15 Hz), 7.85 (1H, dd, J=7.5, 2 Hz), 8.03 (1H, br s), 8.23 (1H,br d, J=7.5 Hz), 8.36 (1H, br s)

Example 24

(1)4-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-1-(2-hydroxyethyl)-2-methoxy-1H-benzimidazolewas obtained from4-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-1-[2-(tert-butyldiphenylsilyloxy)ethyl]-2-methoxy-1H-benzimidazoleaccording to a similar manner to that of

Preparation 13-(5).

NMR (CDCl₃, δ): 2.21 (3H, s), 3.27 (3H, s), 3.69 (1H, dd, J=17, 4 Hz),3.87-4.00 (3H, m), 4.09-4.19 (5H, m), 5.64 (2H, s), 6.47 (1H, d, J=15Hz), 6.75 (1H, br s), 6.85 (1H, d, J=7.5 Hz), 6.94 (1H, d, J=7.5 Hz),7.10 (1H, t, J=7.5 Hz), 7.30 (1H, d, J=7.5 Hz), 7.48 (1H, d, J=7.5 Hz),7.51 (1H, d, J=15 Hz), 7.82 (1H, br d, J=7.5 Hz), 8.09 (1H, br s), 8.19(1H, br d, J=7.5 Hz), 8.30 (1H, br s)

(2)7-[3-[N-[(E)-3-(6-Acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-1-(2-hydroxyethyl)-2-methoxy-1H-benzimidazolewas obtained from7-[3-[N-[(E)-3-(6-acetamidopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-1-[2-(tert-butyldiphenylsilyloxy)ethyl]-2-methoxy-1H-benzimidazoleaccording to a similar manner to that of

Preparation 13-(5).

NMR (CDCl₃, δ): 2.21 (3H, s), 3.29 (3H, s), 3.64-3.74 (3H, m), 3.80 (1H,d, J=5 Hz), 4.12-4.21 (5H, m), 5.43 (1H, d, J=10 Hz), 5.49 (1H, d, J=10Hz), 6.45 (1H, d, J=15 Hz), 6.78 (1H, br t, J=5 Hz), 6.81 (1H, d, J=7.5Hz), 7.11 (1H, t, J=7.5 Hz), 7.24 (1H, d, J=7.5 Hz), 7.36 (1H, d, J=7.5Hz), 7.53 (1H, d, J=15 Hz), 7.58 (1H, d, J=7.5 Hz), 7.84 (1H, br d,J=7.5 Hz), 8.02 (1H, br s), 8.22 (1H, br d, J=7.5 Hz), 8.35 (1H, br s)

Example 25

To a solution of4-[3-[N-[(E)-3-(6-ethoxycarbonylpyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole(304 mg) in ethanol was added 1N sodium hydroxide solution (0.5 ml), andthe mixture was stirred for 1.5 hours at ambient temperature. Thesolvent was removed, water was added to the residue. The mixture wasadjusted to pH 4 with 1N hydrochloric acid and extracted withchloroform. The extract was dried and evaporated in vacuo. Acetonitrilewas added to the residue, and the residue was collected by filtration togive4-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole(195 mg).

NMR (CDCl₃ --CD₃ OD, δ): 3.25 (3H, s), 3.53-3.68 (4H, m), 4.00 (1H, d,J=16 Hz), 4.14 (3H, s), 5.52-5.63 (2H, m), 6.76-6.96 (3H, m), 7.15 (1H,t, J=8 Hz), 7.48-7.61 (4H, m), 8.02-8.20 (2H, m)

Example 26

To a solution of4-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole(90 mg) and 4-aminopyridine (14.3 mg) in N,N-dimethylformamide (2 ml)were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride(31.7 mg) and 1-hydroxybenzotriazole (26.4 mg) at ambient temperature,and after standing for 1 day, the mixture was stirred for 8 hours at 50°C. To the mixture was added water, and extracted with ethyl acetate. Theextract was washed with saturated sodium bicarbonate solution and brine,dried over magnesium sulfate and evaporated in vacuo. The residue waspurified by preparative thin layer chromatography (chloroform:methanol,12:1, v/v) to give4-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(4-pyridylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole(7.8 mg).

NMR (CDCl₃, δ): 3.27 (3H, s), 3.56 (3H, s), 3.61 (1H, dd, J=4, 18 Hz),3.96 (1H, dd, J=4, 18 Hz), 4.19 (3H, s), 5.65 (2H, s), 6.67 (1H, d, J=16Hz), 6.81-6.90 (3H, m), 7.11 (1H, t, J=8 Hz), 7.30 (1H, d, J=8 Hz), 7.48(1H, d, J=8 Hz), 7.58-7.76 (3H, m), 7.98-8.07 (1H, m), 8.27 (1H, d, J=8Hz), 8.48-8.73 (3H, m)

Example 27

4-[2,6-Dichloro-3-[N-methyl-N-[(E)-3-[6-(2-pyridylcarbamoyl)pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazolewas obtained from4-[3-[N-[(E)-3-(6-carboxypyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazoleand 2-aminomethylpyridine according to a similar manner to that ofExample 26.

NMR (CDCl₃, δ): 3.28 (3H, s), 3.53 (3H, s), 3.69 (1H, dd, J=4, 18 Hz),3.95 (1H, dd, J=4, 18 Hz), 4.20 (3H, s), 4.80 (2H, d, J=5 Hz), 5.66 (2H,s), 6.62 (1H, d, J=16 Hz), 6.73 (1H, t-like), 6.83-6.88 (2H, m), 7.11(1H, t, J=8 Hz), 7.21 (1H, dd, J=6, 8 Hz), 7.27-7.36 (2H, m), 7.49 (1H,d, J=8 Hz), 7.62 (1H, d, J=16 Hz), 7.68 (1H, t, J=8 Hz), 7.96 (1H, d,J=8 Hz), 8.22 (1H, d, J=8 Hz), 8.61 (1H, d, J=5 Hz), 8.69 (1H, d, J=2Hz), 8.90 (1H, t-like)

Example 28

To a solution of4-[3-[N-[(E)-3-(6-aminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole(100 mg) and triethylamine (53.3 mg) in dichloromethane (2 ml) was added2-methyl-3-pyridinecarbonyl chloride hydrochloride (74.2 mg) underice-cooling, and the mixture was stirred for 15 minutes at the sametemperature and then for 3 hours at ambient temperature. The reactionmixture was concentrated, and the residue was dissolved in methanol (3ml). To the solution was added 1N sodium hydroxide solution (0.5 ml),and the mixture was stirred for 1 hour. Chloroform was added to thereaction mixture, and the solution was washed with water and brine,dried over magnesium sulfate and evaporated in vacuo. The residue waspurified by preparative thin layer chromatography (chloroform:methanol,10:1, v/v) to give4-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(2-methylpyridin-3-carboxamido)pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole(99 mg).

NMR (CDCl₃, δ): 2.75 (3H, s), 3.28 (3H, s), 3.52 (3H, s), 3.68 (1H, dd,J=17, 4 Hz), 3.94 (1H, d, J=14, 5 Hz), 4.18 (3H, s), 5.65 (2H, s), 6.50(1H, d, J=15 Hz), 6.70 (1H, br s), 6.80-6.89 (2H, m), 7.11 (1H, t, J=7.5Hz), 7.20-7.33 (2H, m), 7.48 (1H, d, J=7.5 Hz), 7.53 (1H, d, J=15 Hz),7.84 (1H, br d, J=7.5 Hz), 7.92 (1H, br dd, J=7.5, 3 Hz), 8.32-8.46 (3H,m), 8.63 (12H, br d, J=2 Hz)

Example 29

(1) A solution of 2-hydroxy-3-methoxybenzaldehyde (6.08 g), ethylbromoacetate (4.9 ml) and potassium carbonate (12.14 g) inN,N-dimethylformamide (30 ml) was stirred for 2 hours at ambienttemperature. Water was added to the reaction mixture, and the resultingprecipitates were collected by filtration and recrystallized withethanol to give 2-ethoxycarbonylmethoxy-3-methoxybenzaldehyde (5.04 g).

mp: 75.1-76.2° C.

NMR (CDCl₃, δ): 1.28 (3H, t, J=7.5 Hz), 3.90 (3H, s), 4.23 (2H, q, J=7.5Hz), 4.84 (2H, s), 7.15 (2H, d, J=7.5 Hz), 7.46 (1H, t, J=5 Hz), 10.46(1H, s)

(2) A solution of 2-ethoxycarbonylmethoxy-3-methoxybenzaldehyde (2.00 g)and potassium tert-butoxide (963 mg) in tetrahydrofuran (20 ml) wasstirred for 1 hour under ice-cooling. Water was added to the reactionmixture, and the solution was neutralized with 1N hydrochloric acid andextracted with ethyl acetate. The extract was washed with water andbrine, dried over magnesium sulfate and evaporated in vacuo. The residuewas purified by preparative thin layer chromatography (n-hexane:ethylacetate=7:1, v/v) to give 2-ethoxycarbonyl-7-methoxybenzofuran (360 mg).

mp: 85° C.

NMR (CDCl₃, δ): 1.42 (3H, t, J=7.5 Hz), 4.04 (3H, s), 4.45 (2H, q, J=7.5Hz), 6.92 (1H, dd, J=7 and 4 Hz), 7.18-7.30 (2H, m), 7.54 (1H, s)

(3) A mixture of 2-ethoxycarbonyl-7-methoxybenzofuran (360 mg), lithiumborohydride (36 mg) in tetrahydrofuran (4 ml) was stirred at ambienttemperature overnight and then for 8 hours at 50° C. Saturated ammoniumchloride solution was added to the reaction mixture, and the solutionwas extracted with ethyl acetate. The extract was washed with saturatedammonium chloride solution and brine, dried over magnesium sulfate andevaporated in vacuo. The residue was purified by flash chromatography(n-hexane-ethyl acetate) to give 2-hydroxymethyl-7-methoxybenzofuran(310 mg).

NMR (CDCl₃, δ): 1.98 (1H, t, J=6 Hz), 4.01 (3H, s), 4.79 (1H, d, J=6Hz), 6.67 (1H, s), 6.81 (1H, m), 7.12 (1H, dd, J=8, 5 Hz), 7.18 (1H, dd,J=8, 5 Hz)

(4) A mixture of 2-hydroxymethyl-7-methoxybenzofuran (300 mg), sodiumcyanoborohydride (796 mg) and zinc iodide (809 mg) in dichloroethane (10ml) was stirred for 2 hours at ambient temperature and then refluxedovernight. Chloroform and water were added to the reaction mixture, andthe separated organic layer was washed with brine, dried over magnesiumsulfate and evaporated in vacuo. The residue was purified by flashchromatography (n-hexane:ethyl acetate 15:1, v/v) to give7-methoxy-2-methylbenzofuran (95 mg).

NMR (CDCl₃, δ): 2.48 (3H, s), 4.00 (3H, s), 6.36 (1H, br s), 6.73 (1H,dd, J=17, 4 Hz), 7.07-7.13 (2H, m), 7.26 (1H, s)

(5) 7-Hydroxy-2-methylbenzofuran was obtained according to a similarmanner to that of Preparation 1-(4).

NMR (CDCl₃, δ): 2.46 (3H, s), 5.22 (1H, s), 6.37 (1H, br s), 6.70-6.81(1H, m), 6.99-7.11 (2H, m)

(6)7-[3-(N-Acetyl-N-methylamino)-2,6-dichlorobenzyloxy]-2-methylbenzofuranwas obtained from 7-hydroxy-2-methylbenzofuran and3-(N-acetyl-N-methylamino)-2,6-dichlorobenzyl bromide according to asimilar manner to that of Example 9.

mp: 114-116° C.

NMR (CDCl₃, δ): 1.83 (3H, s), 2.46 (3H, s), 3.20 (3H, s), 5.54 (2H, s),6.48 (1H, br s), 6.90 (1H, dd, J=6, 3 Hz), 7.06-7.18 (2H, m), 7.28 (1H,d, J=8 Hz), 7.56 (1H, d, J=8 Hz)

We claim:
 1. A heterocyclic compound of the formula: ##STR12## wherein agroup of the formula: ##STR13## is a group of the formula: ##STR14## Xis N--R⁵, R¹ is lower alkyl, halo(lower)alkyl, loweralkylamino(lower)alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl,lower alkoxy, lower alkylthio, lower alkylamino, acyl(lower)alkyl, acyl,hydroxy, mercapto, aryl or ar(lower)alkyl,R⁵ is hydrogen, lower alkyl,halo(lower)alkyl, lower alkylamino(lower)alkyl, hydroxy(lower)alkyl,lower alkoxy(lower)alkyl, lower alkoxy, lower alkylthio, loweralkylamino, acyl(lower)alkyl, acyl, aryl or ar(lower)alkyl, R² ishydrogen, halogen, lower alkyl or lower alkoxy, R³ is halogen, loweralkyl or lower alkoxy, R⁴ is a group of the formula: ##STR15## in whichR⁶ is hydrogen or lower alkyl, and R⁷ is an amino acid residuesubstituted with a substituent selected from the group consisting ofoptionally substituted pyridyl(lower)alkanoyl,pyridyl(lower)alkoxy-ar(lower)alkenoyl, pyridyl-ar(lower)alkenoyloptionally having oxo, pyridyl(lower)alkyl-ar(lower)alkenoyl,pyridyl(lower)alkenyl-ar(lower)alkenoyl, optionally substitutedpyridyl(lower)alkanoylamino-ar(lower)alkenoyl, optionally substitutedpyridylcarbonylamino-ar(lower)alkenoyl, N-(loweralkanoyl)-N-(pyridyl(lower)alkyl)amino-ar(lower)alkenoyl,N-(lower(pyridylcarbonyl)-N-(loweralkoxy(lower)alkyl)amino-ar(lower)alkenoyl,pyridylureido-ar(lower)alkenoyl,pyridyl(lower)alkylcarbamoyl-ar(lower)-alkenoyl,N-(pyridyl(lower)alkyl)-N-(lower alkyl)carbamoyl-ar(lower alkenoyl,pyridylcarbamoyl-ar(lower)alkenoyl, optionally substitutedpyridylcarbonyl-ar(lower)alkenoyl, pyridyl(lower)alkenoyl,pyridyl(lower)alkenyl-pyridyl(lower)alkenoyl, loweralkanoyl-pyridyl(lower)alkenoyl, pyridylthio(lower)alkanoyl,amino-pyridyl(lower)alkenoyl, lower alkylamino-pyridyl(lower)alkenoyl,lower alkanoylamino-pyridyl(lower)alkenoyl in which the pyridyl groupmay be substituted with lower alkyl or lower alkoxy, loweralkanoylamino(lower)alkanoylamino-pyridyl(lower)alkenoyl, loweralkenoylamino-pyridyl(lower)alkenoyl,pyridyl(lower)alkanoylamino-pyridyl(lower)alkenoyl,pyridylcarbonylamino-pyridyl(lower)alkenoyl which may be substitutedwith lower alkyl, loweralkoxycarbonyl(lower)alkanoylamino-pyridyl(lower)alkenoyl, loweralkoxy(lower)alkanoylamino-pyridyl(lower)alkenoyl, loweralkylureido-pyridyl(lower)alkenoyl, carboxy-pyridyl(lower)alkenoyl,lower alkoxycarbonyl-pridyl(lower)alkenoyl, loweralkylcarbamoyl-pridyl(lower)alkenoyl, loweralkoxy(lower)alkylcarbamoyl-pyridyl(lower)alkenoyl,hydroxy(lower)alkylcarbamoyl-pyridyl(lower)alkenoyl,pyridylcarbamoyl-pyridyl(lower)alkenoyl,pyridyl(lower)alkylcarbamoyl-pyridyl-(lower)alkenoyl,pyridylcarbonyl-pyridyl(lower)alkenoyl, loweralkenylcarbamoyl-pyridyl(lower)alkenoyl, loweralkenylcarbamoyl-pyridyl(lower)alkenoyl, optionally substitutedpyridylcarbonyl, pyridylcarbonyl-arylcarbamoyl,pyridylcarbonylamino-arylcarbamoyl,pridyl(lower)alkanoylamino-arylcarbamoyl, pyridyl-arylcarbamoyloptionally having oxo, pyridylcarbonyl-arylcarbamoyl having lower alkyl,pyridylcarbonyl-arylcarbamoyl having aryl, pyridylcarbonyl-arylcarbamoylhaving a pyridyl group, pyridylcarbonyl-arylcarbamoyl having loweralkanoyl, pyridylcarbonyl-arylcarbamoyl having lower alkoxycarbonyl,pyridylcarbonyl-arylcarbamoyl having lower alkylamino,pyridylcarbonyl-arylcarbamoyl having lower alkylcarbamoyl,pyridylcarbamoyl-arylcarbamoyl, N-(pyridyl)-N-(loweralkyl)carbamoyl-arylcarbamoyl,pyridyl(lower)alkylcarbamoyl-arylcarbamoyl,N-(pyridyl(lower)alkyl)-N-(lower alkyl)carbamoyl-arylcarbamoyl,N-(pyridyl(lower)alkyl)-N-(loweralkoxy(lower)alkyl)carbamoyl-arylcarbamoyl, pyridylcarbamoyl,pyridyl(lower)alkylcarbamoyl, amino acid residue substituted with apyridyl group and amino acid residue substituted withpyridyl(lower)alkyl, and A is lower alkylene, or a salt thereof.
 2. Acompound of claim 1, whereina group of the formula: ##STR16## is a groupof the formula: ##STR17##
 3. A compound of claim 2, wherein R⁵ is alower alkyl,R² is hydrogen, halogen or lower alkyl, R³ is halogen orlower alkyl, and A is lower alkylene.
 4. The heterocyclic compound ofclaim 1, having theformula:4-[3-[N-[(E)-3-(6-acetylaminopyridin-3-yl)-acryloylglycyl]-N-methylamino]-2,6-dimethylbenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole.5. A pharmaceutical composition comprising a compound of claim 1 or itssalt, as an active ingredient, in association with a pharmaceuticallyacceptable excipient.
 6. A method for the prevention or the treatment ofbradykinin or its analogues mediated diseases selected from allergy,inflammation, shock or pain, which comprises administering a compound ofclaim 1 or its salt to a human being or animals.
 7. An agent for theprevention or the treatment of bradykinin or its analogues mediateddiseases selected from allergy, inflammation, shock or pain, whichcomprises a compound of claim 1 or its salt as an active ingredient. 8.A process for preparing a compound of the formula: ##STR18## wherein agroup of the formula: ##STR19## R², R³, R⁴ and A are each as definedbelow, or its salt, which comprises reacting a compound of the formula:##STR20## wherein a group of the formula: ##STR21## is a group of theformula: ##STR22## X is N--R⁵ R¹ is lower alkyl, halo(lower)alkyl, loweralkylamino(lower)alkyl, hydroxy(lower)alkyl, lower alkoxy(lower)alkyl,lower alkoxy, lower alkylthio, lower alkylamino, acyl(lower)alkyl, acyl,hydroxy, mercapto, aryl or ar(lower)alkyl, andR⁵ is hydrogen, loweralkyl, halo(lower)alkyl, lower alkylamino(lower)alkyl,hydroxy(lower)alkyl, lower alkoxy(lower)alkyl, lower alkoxy, loweralkylthio, lower alkylamino, acyl(lower)alkyl, acyl, aryl orar(lower)alkyl, or its salt with a compound of the formula: ##STR23##wherein R² is hydrogen, halogen, lower alkyl, or lower alkoxy, R³ ishalogen, lower alkyl or lower alkoxy, R⁴ is a group of the formula:##STR24## in which R⁶ is hydrogen or lower alkyl, and R⁷ is an aminoacid residue substituted with a substituent selected from the groupconsisting of optionally substituted pyridyl(lower)alkanoyl,pyridyl(lower)alkoxy-ar(lower)alkenoyl, pyridyl-ar(lower)alkenoyloptionally having oxo, pyridyl(lower)alkyl-ar(lower)alkenoyl,pyridyl(lower)alkenyl-ar(lower)alkenoyl, optionally substitutedpyridyl(lower)alkanoylamino-ar(lower)alkenoyl, optionally substitutedpyridylcarbonylamino-ar(lower)alkenoyl, N-(loweralkanoyl)-N-(pyridyl(lower)alkyl)amino-ar(lower)alkenoyl, N-(loweralkoxy(lower)alkanoyl)-N-(pyridyl(lower)alkyl)amino-ar(lower)alkenoyl,N-(pyridylcarbonyl)-N-(lower alkoxy(lower)alkyl)amino-ar(lower)alkenoyl,pyridylureido-ar(lower)alkenoyl,pyridyl(lower)alkylcarbamoyl-ar(lower)-alkenoyl,N-(pyridyl(lower)alkyl)-N-(lower alkyl)carbamoyl-ar(lower)alkenoyl,pyridylcarbamoyl-ar(lower)alkenoyl, optionally substitutedpyridylcarbonyl-ar(lower)alkenoyl, pyridyl(lower)alkenoyl,pyridyl(lower)alkenyl-pyridyl(lower)alkenoyl, loweralkanoyl-pyridyl(lower)alkenoyl, pyridylthio(lower)alkanoyl,amino-pyridyl(lower)alkenoyl, lower alkylamino-pyridyl(lower)alkenoyl,lower alkanoylamino-pyridyl(lower)alkenoyl in which the pyridyl groupmay be substituted with lower alkyl or lower alkoxy, loweralkanoylamino(lower)alkanoylamino-pyridyl-(lower)alkenoyl, loweralkenoylamino-pyridyl(lower)alkenoylpyridyl(lower)alkanoylamino-pyridyl-(lower)alkenoyl,pyridylcarbonylamino-pyridyl(lower)alkenoyl which may be substitutedwith lower alkyl, loweralkoxycarbonyl(lower)alkanoylamino-pyridyl-(lower)alkenoyl, loweralkoxy(lower)alkanoylamino-pyridyl(lower)alkenoyl, loweralkylureido-pyridyl(lower)alkenoyl, carboxy-pyridyl(lower)alkenoyl,lower alkoxycarbonyl-pyridyl(lower)alkenoyl, loweralkylcarbamoyl-pyridyl(lower)alkenoyl, loweralkoxy(lower)alkylcarbamoyl-pyridyl(lower)alkenoyl,hydroxy(lower)alkylcarbamoyl-pyridyl(lower)alkenoyl,pyridylcarbamoyl-pyridyl(lower)alkenoyl,pyridyl(lower)alkylcarbamoyl-pyridyl-(lower)alkenoyl,pyridylcarbonyl-pyridyl(lower)alkenoyl, loweralkenylcarbamoyl-pyridyl(lower)alkenoyl, loweralkenylcarbamoyl-pyridyl(lower)alkenoyl, optionally substitutedpyridylcarbonyl, pyridylcarbonyl-arylcarbamoyl,pyridylcarbonylamino-arylcarbamoyl,pyridyl(lower)alkanoylamino-arylcarbamoyl, pyridyl-arylcarbamoyloptionally having oxo, pyridylcarbonyl-arylcarbamoyl having lower alkyl,pyridylcarbonyl-arylcarbamoyl having aryl, pyridylcarbonyl-arylcarbamoylhaving a pyridyl group, pyridylcarbonyl-arylcarbamoyl having loweralkanoyl, pyridylcarbonyl-arylcarbamoyl having lower alkoxycarbonyl,pyridylcarbonyl-arylcarbamoyl having lower alkylamino,pyridylcarbonyl-arylcarbamoyl having lower alkylcarbamoyl,pyridylcarbamoyl-arylcarbamoyl, N-(pyridyl)-N-(loweralkyl)carbamoyl-arylcarbamoyl,pyridyl(lower)alkylcarbamoyl-arylcarbamoyl,N-(pyridyl(lower)alkyl)-N-(lower alkyl)carbamoyl-arylcarbamoyl,N-(pyridyl(loweralkyl)-N-(lower)alkoxy(lower)alkyl)carbamoyl-arylcarbamoyl,pyridylcarbamoyl, pyridyl(lower)alkylcarbamoyl, amino acid residuesubstituted with a pyridyl group and amino acid residue substituted withpyridyl(lower)alkyl, A is lower alkylene, and Y is a leaving group, orits salt to give a compound of the formula: ##STR25## wherein a group ofthe formula: ##STR26## R², R³, R⁴ and A are each as defined above, orits salt.